chr2-170822115-T-C

Position:

chr2-170822115-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000358196.8(GAD1):c.111T>C(p.His37=) 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
ENST00000358196.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.140

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr2-170822115-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
GAD1	NM_000817.3 linkuse as main transcript	c.111T>C	p.His37=	synonymous_variant	3/17	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8 linkuse as main transcript	c.111T>C	p.His37=	synonymous_variant	3/17	1	NM_000817.3	ENSP00000350928	P1	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

GnomAD3 exomes

AF:

0.394

AC:

96714

AN:

245232

Hom.:

19618

AF XY:

0.401

AC XY:

53102

AN XY:

132532

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 SAS exome

AF:

0.380

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

Gnomad4 AFR exome

AF:

0.181

Gnomad4 AMR exome

AF:

0.337

Gnomad4 ASJ exome

AF:

0.423

Gnomad4 EAS exome

AF:

0.498

Gnomad4 SAS exome

AF:

0.382

Gnomad4 FIN exome

AF:

0.407

Gnomad4 NFE exome

AF:

0.424

Gnomad4 OTH exome

AF:

0.403

GnomAD4 genome

AF:

0.354

AC:

53789

AN:

152018

Hom.:

10293

Cov.:

AF XY:

0.355

AC XY:

26406

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.378

Gnomad4 ASJ

AF:

0.412

Gnomad4 EAS

AF:

0.488

Gnomad4 SAS

AF:

0.384

Gnomad4 FIN

AF:

0.410

Gnomad4 NFE

AF:

0.424

Gnomad4 OTH

AF:

0.383

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Developmental and epileptic encephalopathy 89

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.4

DANN

Benign

0.67

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