Variant 10-26217969-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001134366.2(GAD2):c.264C>A(p.Asn88Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GAD2
NM_001134366.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	3/16	ENST00000376261.8
GAD2	NM_000818.3 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GAD2	ENST00000376261.8 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	3/16	1	NM_001134366.2	P1
GAD2	ENST00000259271.7 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	3/17	1		P1
GAD2	ENST00000428517.2 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	3/4	1
GAD2	ENST00000648567.1 linkuse as main transcript	c.-79C>A		5_prime_UTR_variant	3/17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000204

AC:

AN:

244918

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133244

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1458786

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725564

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

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

Nov 15, 2021

The c.264C>A (p.N88K) alteration is located in exon 3 (coding exon 3) of the GAD2 gene. This alteration results from a C to A substitution at nucleotide position 264, causing the asparagine (N) at amino acid position 88 to be replaced by a lysine (K). 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

-0.28

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

0.014

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.087

Sift

Benign

0.14

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.14

B;B

Vest4

0.59

MutPred

0.47

Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);

MVP

0.49

MPC

0.45

ClinPred

0.19

GERP RS

3.7

Varity_R

0.40

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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