rs1129647

Variant names:

• chr5-161854239-T-C
• rs1129647
• NM_001127644.2:c.156T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-161854239-T-C
• chr5-161854239-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127644.2(GABRA1):​c.156T>C​(p.Gly52Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,596,510 control chromosomes in the GnomAD database, including 55,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4775 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51195 hom.)
• Consequence: GABRA1 NM_001127644.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.550
• Publications: 19 publications found

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRA1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 19

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 13

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-161854239-T-C is Benign according to our data. Variant chr5-161854239-T-C is described in ClinVar as Benign. ClinVar VariationId is 129123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.156T>C	p.Gly52Gly	synonymous_variant	Exon 3 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.156T>C	p.Gly52Gly	synonymous_variant	Exon 3 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36136 AN: 151328 Hom.: 4770 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.264 AC: 66172 AN: 250770 AF XY: 0.268

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.308

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.263 AC: 380104 AN: 1445064 Hom.: 51195 Cov.: 29 AF XY: 0.264 AC XY: 190202 AN XY: 719828

African (AFR) AF: 0.125 AC: 4145 AN: 33140

American (AMR) AF: 0.220 AC: 9844 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6654 AN: 25980

East Asian (EAS) AF: 0.287 AC: 11365 AN: 39558

South Asian (SAS) AF: 0.257 AC: 22073 AN: 85904

European-Finnish (FIN) AF: 0.350 AC: 18668 AN: 53376

Middle Eastern (MID) AF: 0.273 AC: 1569 AN: 5738

European-Non Finnish (NFE) AF: 0.264 AC: 290032 AN: 1096884

Other (OTH) AF: 0.263 AC: 15754 AN: 59824

GnomAD4 genome AF: 0.239 AC: 36146 AN: 151446 Hom.: 4775 Cov.: 32 AF XY: 0.242 AC XY: 17906 AN XY: 74010

African (AFR) AF: 0.129 AC: 5359 AN: 41452

American (AMR) AF: 0.239 AC: 3624 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 926 AN: 3458

East Asian (EAS) AF: 0.303 AC: 1555 AN: 5140

South Asian (SAS) AF: 0.266 AC: 1276 AN: 4800

European-Finnish (FIN) AF: 0.359 AC: 3781 AN: 10530

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18629 AN: 67584

Other (OTH) AF: 0.262 AC: 551 AN: 2106

Alfa AF: 0.257 Hom.: 3156

Bravo AF: 0.224

Asia WGS AF: 0.275 AC: 954 AN: 3478

EpiCase AF: 0.278

EpiControl AF: 0.286

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 40. Only high quality variants are reported. -

not provided Benign:2

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, idiopathic generalized, susceptibility to, 13 Benign:1

Jan 13, 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. -

Developmental and epileptic encephalopathy, 19 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	-0.52
CADD	Benign	6.2
DANN	Benign	0.71
PhyloP100		-0.55
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1129647; hg19: chr5-161281245; COSMIC: COSV50098561; COSMIC: COSV50098561;