4-46250306-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000807.4(GABRA2):c.*2T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,606,202 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: GABRA2 NM_000807.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.529

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-46250306-A-T is Benign according to our data. Variant chr4-46250306-A-T is described in ClinVar as [Benign]. Clinvar id is 3038829.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1882/151744) while in subpopulation AFR AF= 0.043 (1784/41482). AF 95% confidence interval is 0.0413. There are 43 homozygotes in gnomad4. There are 909 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1858 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4	c.*2T>A		3_prime_UTR_variant	10/10	ENST00000381620.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA2	ENST00000381620.9	c.*2T>A		3_prime_UTR_variant	10/10	1	NM_000807.4	P2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1858 AN: 151626 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00435

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00816

GnomAD3 exomes AF: 0.00313 AC: 771 AN: 246274 Hom.: 11 AF XY: 0.00225 AC XY: 300 AN XY: 133350

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000665

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000718

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00131 AC: 1899 AN: 1454458 Hom.: 36 Cov.: 30 AF XY: 0.00110 AC XY: 795 AN XY: 723374

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000280

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.0124 AC: 1882 AN: 151744 Hom.: 43 Cov.: 32 AF XY: 0.0123 AC XY: 909 AN XY: 74154

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.00435

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00807

Alfa AF: 0.00338 Hom.: 0

Bravo AF: 0.0138

Asia WGS AF: 0.00549 AC: 19 AN: 3476

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GABRA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 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	-0.88
Cadd	Benign	2.2
Dann	Benign	0.26

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: rs76026776; hg19: chr4-46252323;