Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals

Table 2 List of missense (and in-frame indels) mutations detected in the GCK gene. All mutations (except p.A11T) were observed in a single individual in our dataset

DNA change	AA change	Poly-Phen2^a	SIFT^b	MutationTaster^c	CADD^d	Age at diagnosis, years	Previously observed in MODY	ExAC AF^e	dbSNP144	ACMG class^f
c.484G > A	p.G162S	Pr.D	tol	del	26.5	13	1 family	─	─	3
c.952G > A	p.G318R	Pos.D	del	del	27.2	14	4 families	─	─	4
c.617C > T	p.T206M	Pr.D	del	del	33	19	13 families	─	─	4
c.238G > A	p.G80S	Pr.D	del	del	32	24	2 families	─	rs193922317	4
c.1349C > T	p.A450V	Pr.D	del	del	29.7	27		─	─	3
c.911T > C	p.L304P	Pr.D	tol	del	24.6	28	3 families	─	─	4
c.559G > T	p.D187Y	Pr.D	del	del	33	28	3 families	─	─	4
c.214G > A	p.G72R	Pr.D	del	del	34	29	18 families	─	rs193922289	5
c.118G > A	p.E40K	Pr.D	del	del	33	30	5 families	─	─	4
c.562G > A	p.A188T	Pr.D	del	del	35	30	22 families	0.0001	rs751279776	4
c.640T > G	p.Y214D	Pr.D	del	del	27.2	33		─	─	3
c.131G > A	p.G44D	Pr.D	del	del	29	34	4 families	─	rs193922279	4
c.572G > A	p.R191Q	Pr.D	del	del	35	37	9 families	─	─	4
c.787_801del	p.263_267del	─	─	─	─	39		─	─	4
c.544G > A	p.V182M	Pr.D	del	del	34	41	12 families	─	rs587780345	5
c.706G > A	p.E236K	Pos.D	del	del	33	42	2 families	─	rs587780347	4
c.394G > A	p.D132N	benign	tol	del	23	56	1 family	0.000015	─	3
c.757G > A	p.V253I	benign	tol	del	18.4	61		0.00006	rs748964205	3
c.31G > A	p.A11T	benign	tol	poly	12.8	32, 45		0.024	rs116093166	2
c.35A > G	p.K12R	benign	tol	poly	16.8	NA		0.000015	rs777958777	3

Reference sequence for GCK: NM_000162
^aPolyPhen2 predictions are probably damaging (Pr.D), possibly damaging (Pos.D) and benign
^bSIFT predictions are deleterious (del) and tolerated (tol)
^cMutationTaster predictions are disease causing (del) and polymorphism (poly)
^dCADD scaled C-scores range from 0 to 30. Higher CADD scores correspond to more deleterious variants; a CADD score of 20 (30) corresponds to the top 1% (0.1%) of deleterious substitutions in the human genome
^eExAC allele frequency is the maximum allele frequency of the variant allele among the different populations
^fACMG classification: 5 = pathogenic, 4 = likely pathogenic and 3 = uncertain significance (see Methods)
AA amino acid, ACMG American College of Medical Genetics, AF allele frequency, dbSNP Single Nucleotide Polymorphism Database, ExAC Exome Aggregation Consortium, NA not available

ISSN: 1741-7015