Variant 10-26219128-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001134366.2(GAD2):c.372A>C(p.Lys124Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

GAD2
NM_001134366.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038317144).

BS2

High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2 linkuse as main transcript	c.372A>C	p.Lys124Asn	missense_variant	4/16	ENST00000376261.8
GAD2	NM_000818.3 linkuse as main transcript	c.372A>C	p.Lys124Asn	missense_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8 linkuse as main transcript	c.372A>C	p.Lys124Asn	missense_variant	4/16	1	NM_001134366.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000956

GnomAD3 exomes

AF:

0.0000877

AC:

AN:

250948

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.0000582

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:

0.0000287

AC:

AN:

1461242

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726854

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.000112

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000374

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.000327

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:

0.000946

Alfa

AF:

0.0000749

Hom.:

Bravo

AF:

0.000495

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.372A>C (p.K124N) alteration is located in exon 4 (coding exon 4) of the GAD2 gene. This alteration results from a A to C substitution at nucleotide position 372, causing the lysine (K) at amino acid position 124 to be replaced by an asparagine (N). 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

0.24

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;D;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.89

M_CAP

Benign

0.014

MetaRNN

Benign

0.038

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

N;N;.

REVEL

Benign

0.14

Sift

Benign

0.043

D;D;.

Sift4G

Benign

0.20

T;T;.

Polyphen

0.055

B;B;.

Vest4

0.37

MutPred

0.19

Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;

MVP

0.46

MPC

0.52

ClinPred

0.068

GERP RS

-1.1

Varity_R

0.47

gMVP

0.53

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