Genetic Variant GAD2:p.Ala28Val (chr10-26217616-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001134366.2(GAD2):c.83C>T(p.Ala28Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GAD2
NM_001134366.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3584249).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2 link	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 16	ENST00000376261.8	NP_001127838.1	Q05329Q5VZ30
GAD2	NM_000818.3 link	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 17		NP_000809.1	Q05329Q5VZ30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAD2	ENST00000376261.8 link	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 16	1	NM_001134366.2	ENSP00000365437.3	Q05329
GAD2	ENST00000259271.7 link	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 17	1		ENSP00000259271.3	Q05329
GAD2	ENST00000428517.2 link	n.83C>T		non_coding_transcript_exon_variant	Exon 2 of 4	1		ENSP00000390434.2	Q5VZ31
GAD2	ENST00000648567 link	c.-260C>T		5_prime_UTR_variant	Exon 2 of 17			ENSP00000498009.1	A0A3B3IU09

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247624

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134200

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460644

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83C>T (p.A28V) alteration is located in exon 2 (coding exon 2) of the GAD2 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

0.079

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

L;L

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.48

N;N

REVEL

Benign

0.088

Sift

Benign

0.048

D;D

Sift4G

Benign

0.19

T;T

Polyphen

0.44

B;B

Vest4

0.57

MVP

0.50

MPC

1.2

ClinPred

0.55

GERP RS

4.8

Varity_R

0.14

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over