chr10-26224610-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.67

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 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_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2 link	c.683T>C	p.Ile228Thr	missense_variant	Exon 6 of 16	ENST00000376261.8	NP_001127838.1	Q05329Q5VZ30
GAD2	NM_000818.3 link	c.683T>C	p.Ile228Thr	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.683T>C	p.Ile228Thr	missense_variant	Exon 6 of 16	1	NM_001134366.2	ENSP00000365437.3	Q05329
GAD2	ENST00000259271.7 link	c.683T>C	p.Ile228Thr	missense_variant	Exon 6 of 17	1		ENSP00000259271.3	Q05329
GAD2	ENST00000648567.1 link	c.341T>C	p.Ile114Thr	missense_variant	Exon 6 of 17			ENSP00000498009.1	A0A3B3IU09
GAD2	ENST00000376248.1 link	n.530T>C		non_coding_transcript_exon_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.00263

AC:

661

AN:

251318

AF XY:

0.00225

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 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

African (AFR)

AF:

0.00122

AC:

AN:

33478

American (AMR)

AF:

0.0132

AC:

589

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.00517

AC:

205

AN:

39686

South Asian (SAS)

AF:

0.00106

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000935

AC:

104

AN:

1111848

Other (OTH)

AF:

0.00113

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00135

AC:

206

AN:

152340

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41582

American (AMR)

AF:

0.00784

AC:

120

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00674

AC:

AN:

5190

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000664

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.5

H;H;.

PhyloP100

7.7

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

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr10-26224610-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over