4-46312576-T-C

Position:

• chr4-46312576-T-C

Variant summary

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

The NM_000807.4(GABRA2):​c.396A>G​(p.Lys132=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,595,942 control chromosomes in the GnomAD database, including 145,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11580 hom., cov: 32)
  • Exomes 𝑓: 0.43 (133934 hom.)
• Consequence: GABRA2 NM_000807.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.110

Genes affected

GABRA2 (HGNC:4076): (gamma-aminobutyric acid type A receptor subunit alpha2) 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. At least 16 distinct subunits of GABA-A receptors have been identified. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-46312576-T-C is Benign according to our data. Variant chr4-46312576-T-C is described in ClinVar as [Benign]. Clinvar id is 1168077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.396A>G	p.Lys132=	synonymous_variant	5/10	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.396A>G	p.Lys132=	synonymous_variant	5/10	1	NM_000807.4	ENSP00000371033	P2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57479 AN: 151908 Hom.: 11565 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.373

GnomAD3 exomes AF: 0.404 AC: 95718 AN: 237012 Hom.: 20498 AF XY: 0.397 AC XY: 50804 AN XY: 128098

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.518

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.425 AC: 613714 AN: 1443916 Hom.: 133934 Cov.: 31 AF XY: 0.419 AC XY: 300932 AN XY: 718114

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.492

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.486

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.378 AC: 57511 AN: 152026 Hom.: 11580 Cov.: 32 AF XY: 0.379 AC XY: 28136 AN XY: 74302

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.524

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.372

Alfa AF: 0.398 Hom.: 5931

Bravo AF: 0.383

Asia WGS AF: 0.368 AC: 1279 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

GABRA2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.7
DANN	Benign	0.63

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: rs279858; hg19: chr4-46314593; COSMIC: COSV62914124;