2-170822115-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000817.3(GAD1):c.111T>C(p.His37His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,610,348 control chromosomes in the GnomAD database, including 136,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10293 hom., cov: 32)

Exomes 𝑓: 0.41 ( 126414 hom. )

Consequence

GAD1
NM_000817.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.140

Publications

29 publications found

Variant links:

Genes affected

GAD1 (HGNC:4092): (glutamate decarboxylase 1) 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 autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

GAD1 Gene-Disease associations (from GenCC):

early infantile epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 89
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
spastic quadriplegic cerebral palsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cerebral palsy, spastic quadriplegic, 1
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GAD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 2-170822115-T-C is Benign according to our data. Variant chr2-170822115-T-C is described in ClinVar as [Benign]. Clinvar id is 332226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3 link	c.111T>C	p.His37His	synonymous_variant	Exon 3 of 17	ENST00000358196.8	NP_000808.2	Q99259-1A0A0S2Z3V5Q8IVA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8 link	c.111T>C	p.His37His	synonymous_variant	Exon 3 of 17	1	NM_000817.3	ENSP00000350928.3		Q99259-1

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53787

AN:

151902

Hom.:

10295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.488

Gnomad SAS

AF:

0.383

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.424

Gnomad OTH

AF:

0.383

GnomAD2 exomes

AF:

0.394

AC:

96714

AN:

245232

AF XY:

0.401

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.331

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.481

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.426

Gnomad OTH exome

AF:

0.408

GnomAD4 exome

AF:

0.414

AC:

603037

AN:

1458330

Hom.:

126414

Cov.:

AF XY:

0.414

AC XY:

300001

AN XY:

725066

show subpopulations

African (AFR)

AF:

0.181

AC:

6066

AN:

33454

American (AMR)

AF:

0.337

AC:

14924

AN:

44340

Ashkenazi Jewish (ASJ)

AF:

0.423

AC:

11039

AN:

26080

East Asian (EAS)

AF:

0.498

AC:

19755

AN:

39634

South Asian (SAS)

AF:

0.382

AC:

32675

AN:

85604

European-Finnish (FIN)

AF:

0.407

AC:

21496

AN:

52822

Middle Eastern (MID)

AF:

0.404

AC:

2331

AN:

5768

European-Non Finnish (NFE)

AF:

0.424

AC:

470481

AN:

1110368

Other (OTH)

AF:

0.403

AC:

24270

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

18118

36235

54353

72470

90588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.354

AC:

53789

AN:

152018

Hom.:

10293

Cov.:

AF XY:

0.355

AC XY:

26406

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.188

AC:

7780

AN:

41472

American (AMR)

AF:

0.378

AC:

5787

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1428

AN:

3470

East Asian (EAS)

AF:

0.488

AC:

2518

AN:

5162

South Asian (SAS)

AF:

0.384

AC:

1852

AN:

4822

European-Finnish (FIN)

AF:

0.410

AC:

4330

AN:

10566

Middle Eastern (MID)

AF:

0.322

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.424

AC:

28794

AN:

67918

Other (OTH)

AF:

0.383

AC:

810

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

1786

3572

5359

7145

8931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.404

Hom.:

4868

Bravo

AF:

0.345

Asia WGS

AF:

0.419

AC:

1456

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy 89

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.4

(source)

DANN

Benign

0.67

PhyloP100

-0.14

PromoterAI

-0.051

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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2-170822115-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