Genetic Variant GAD2:p.Gly232Ala (chr10-26224622-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001134366.2(GAD2):c.695G>C(p.Gly232Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. G232E) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GAD2
NM_001134366.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.27

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23657444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2 link	c.695G>C	p.Gly232Ala	missense_variant	Exon 6 of 16	ENST00000376261.8	NP_001127838.1	Q05329Q5VZ30
GAD2	NM_000818.3 link	c.695G>C	p.Gly232Ala	missense_variant	Exon 6 of 17		NP_000809.1	Q05329Q5VZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAD2	ENST00000376261.8 link	c.695G>C	p.Gly232Ala	missense_variant	Exon 6 of 16	1	NM_001134366.2	ENSP00000365437.3	Q05329
GAD2	ENST00000259271.7 link	c.695G>C	p.Gly232Ala	missense_variant	Exon 6 of 17	1		ENSP00000259271.3	Q05329
GAD2	ENST00000648567.1 link	c.353G>C	p.Gly118Ala	missense_variant	Exon 6 of 17			ENSP00000498009.1	A0A3B3IU09
GAD2	ENST00000376248.1 link	n.542G>C		non_coding_transcript_exon_variant	Exon 4 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461198

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111466

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

0.096

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.0075

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;.

PhyloP100

6.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.98

N;N;.

REVEL

Benign

0.075

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.48

T;T;.

Polyphen

0.0040

B;B;.

Vest4

0.34

MutPred

0.47

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;

MVP

0.20

MPC

0.50

ClinPred

0.82

GERP RS

5.2

Varity_R

0.35

gMVP

0.85

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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