10-26223976-A-C

Variant names:

• chr10-26223976-A-C
• rs553646520
• NM_001134366.2:c.610A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001134366.2(GAD2):​c.610A>C​(p.Met204Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M204V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: GAD2 NM_001134366.2 missense, splice_region
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

GAD2 (HGNC:4093): (glutamate decarboxylase 2) This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.610A>C	p.Met204Leu	missense_variant, splice_region_variant	Exon 5 of 16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.610A>C	p.Met204Leu	missense_variant, splice_region_variant	Exon 5 of 17		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.610A>C	p.Met204Leu	missense_variant, splice_region_variant	Exon 5 of 16	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.610A>C	p.Met204Leu	missense_variant, splice_region_variant	Exon 5 of 17	1		ENSP00000259271.3
GAD2	ENST00000648567.1	c.268A>C	p.Met90Leu	missense_variant, splice_region_variant	Exon 5 of 17			ENSP00000498009.1
GAD2	ENST00000376248.1	n.457A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151224 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251062 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 25

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151342 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73874

African (AFR) AF: 0.0000243 AC: 1 AN: 41146

American (AMR) AF: 0.00 AC: 0 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67896

Other (OTH) AF: 0.00 AC: 0 AN: 2084

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N;.
REVEL	Benign	0.22
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.18	T;T;.
Polyphen		0.14	B;B;.
Vest4		0.82
MutPred		0.65		Loss of catalytic residue at M204 (P = 0.0255);Loss of catalytic residue at M204 (P = 0.0255);.;
MVP		0.72
MPC		0.40
ClinPred		0.39	T
GERP RS		5.7
Varity_R		0.68
gMVP		0.91
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs553646520; hg19: chr10-26512905;