rs11542313

Positions:

• chr2-170822115-T-C
• chr2-170822115-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000817.3(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 NM_000817.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.140

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]

ACMG classification

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	UniProt
GAD1	NM_000817.3	c.111T>C	p.His37=	synonymous_variant	3/17	ENST00000358196.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53787 AN: 151902 Hom.: 10295 Cov.: 32

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

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.: 41 AF XY: 0.414 AC XY: 300001 AN XY: 725066

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.: 32 AF XY: 0.355 AC XY: 26406 AN XY: 74300

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

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

Other links and lift over

dbSNP: rs769404; hg19: chr2-171678625; COSMIC: COSV60153936; COSMIC: COSV60153936;