dbSNP rs374182148: GAD2:p.Gly50Arg (chr10-26217853-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001134366.2(GAD2):c.148G>A(p.Gly50Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GAD2
NM_001134366.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.98

Publications

0 publications found

Variant links:

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]

GAD2 links:

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ACMG classification

Classification was made for transcript

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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 3 of 16	ENST00000376261.8	NP_001127838.1	Q05329Q5VZ30
GAD2	NM_000818.3 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 3 of 17		NP_000809.1	Q05329Q5VZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAD2	ENST00000376261.8 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 3 of 16	1	NM_001134366.2	ENSP00000365437.3	Q05329
GAD2	ENST00000259271.7 link	c.148G>A	p.Gly50Arg	missense_variant	Exon 3 of 17	1		ENSP00000259271.3	Q05329
GAD2	ENST00000428517.2 link	n.148G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000390434.2	Q5VZ31
GAD2	ENST00000648567.1 link	c.-195G>A		5_prime_UTR_variant	Exon 3 of 17			ENSP00000498009.1	A0A3B3IU09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000138

AC:

AN:

1453304

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33268

American (AMR)

AF:

0.00

AC:

AN:

43724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108052

Other (OTH)

AF:

0.00

AC:

AN:

59934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.0036

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

.;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.81

L;L

PhyloP100

5.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.33

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.49

T;T

Sift4G

Benign

0.096

T;T

Polyphen

0.0050

B;B

Vest4

0.53

MutPred

0.73

Gain of MoRF binding (P = 0.053);Gain of MoRF binding (P = 0.053);

MVP

0.86

MPC

1.1

ClinPred

0.55

GERP RS

5.8

Varity_R

0.25

gMVP

0.51

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.62

Position offset: 2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over