Variant 10-26224610-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001134366.2(GAD2):c.683T>C(p.Ile228Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 1,613,996 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 12 hom. )

Consequence

GAD2
NM_001134366.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.67

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0107836425).

BP6

Variant 10-26224610-T-C is Benign according to our data. Variant chr10-26224610-T-C is described in ClinVar as [Benign]. Clinvar id is 771433.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2 linkuse as main transcript	c.683T>C	p.Ile228Thr	missense_variant	6/16	ENST00000376261.8
GAD2	NM_000818.3 linkuse as main transcript	c.683T>C	p.Ile228Thr	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GAD2	ENST00000376261.8 linkuse as main transcript	c.683T>C	p.Ile228Thr	missense_variant	6/16	1	NM_001134366.2	P1
GAD2	ENST00000259271.7 linkuse as main transcript	c.683T>C	p.Ile228Thr	missense_variant	6/17	1		P1
GAD2	ENST00000648567.1 linkuse as main transcript	c.341T>C	p.Ile114Thr	missense_variant	6/17
GAD2	ENST00000376248.1 linkuse as main transcript	n.530T>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00673

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00263

AC:

661

AN:

251318

Hom.:

AF XY:

0.00225

AC XY:

305

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00593

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000800

AC:

1170

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000787

AC XY:

572

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.0132

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00517

Gnomad4 SAS exome

AF:

0.00106

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.0000935

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00135

AC:

206

AN:

152340

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.00784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00674

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000526

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00216

AC:

262

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.5

H;H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.8

D;D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

0.49

P;P;.

Vest4

0.80

MVP

0.48

MPC

1.0

ClinPred

0.069

GERP RS

5.2

Varity_R

0.89

gMVP

0.97

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