NM_001127644.2:c.1059+15G>A

Variant names:

• chr5-161895883-G-A
• rs2279020
• NM_001127644.2:c.1059+15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127644.2(GABRA1):​c.1059+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,601,462 control chromosomes in the GnomAD database, including 336,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30064 hom., cov: 32)
  • Exomes 𝑓: 0.65 (306341 hom.)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.302
• Publications: 44 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-161895883-G-A is Benign according to our data. Variant chr5-161895883-G-A is described in ClinVar as Benign. ClinVar VariationId is 93431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.1059+15G>A		intron_variant	Intron 9 of 9	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.1059+15G>A		intron_variant	Intron 9 of 9	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes AF: 0.625 AC: 95015 AN: 151930 Hom.: 30025 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.625

GnomAD2 exomes AF: 0.621 AC: 156072 AN: 251212 AF XY: 0.616

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.650

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.648 AC: 939033 AN: 1449414 Hom.: 306341 Cov.: 30 AF XY: 0.644 AC XY: 465075 AN XY: 721866

African (AFR) AF: 0.595 AC: 19738 AN: 33198

American (AMR) AF: 0.714 AC: 31932 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 16994 AN: 26070

East Asian (EAS) AF: 0.479 AC: 18983 AN: 39624

South Asian (SAS) AF: 0.567 AC: 48754 AN: 86006

European-Finnish (FIN) AF: 0.556 AC: 29682 AN: 53360

Middle Eastern (MID) AF: 0.590 AC: 3383 AN: 5736

European-Non Finnish (NFE) AF: 0.665 AC: 731437 AN: 1100726

Other (OTH) AF: 0.636 AC: 38130 AN: 59982

GnomAD4 genome AF: 0.626 AC: 95111 AN: 152048 Hom.: 30064 Cov.: 32 AF XY: 0.622 AC XY: 46227 AN XY: 74286

African (AFR) AF: 0.599 AC: 24836 AN: 41464

American (AMR) AF: 0.704 AC: 10758 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2245 AN: 3472

East Asian (EAS) AF: 0.463 AC: 2393 AN: 5170

South Asian (SAS) AF: 0.562 AC: 2710 AN: 4824

European-Finnish (FIN) AF: 0.554 AC: 5843 AN: 10556

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44316 AN: 67968

Other (OTH) AF: 0.625 AC: 1317 AN: 2106

Alfa AF: 0.642 Hom.: 59315

Bravo AF: 0.634

Asia WGS AF: 0.531 AC: 1850 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2013

Eurofins Ntd Llc (ga)

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 85% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 79. Only high quality variants are reported. -

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

- -

not provided Benign:1

Mar 03, 2015

GeneDx

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	-0.85
CADD	Benign	0.96
DANN	Benign	0.17
PhyloP100		0.30
Mutation Taster		=100/0	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: rs2279020; hg19: chr5-161322889; COSMIC: COSV50100429; COSMIC: COSV50100429;