chr4-46261847-T-A

Variant names:

• chr4-46261847-T-A
• rs10938435
• ENST00000515082.5:c.*34A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000515082.5(GABRA2):​c.*34A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,218,320 control chromosomes in the GnomAD database, including 200,079 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (20146 hom., cov: 31)
  • Exomes 𝑓: 0.58 (179933 hom.)
• Consequence: GABRA2 ENST00000515082.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• Publications: 2 publications found

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]

GABRA2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 78

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.1059+79A>T		intron_variant	Intron 9 of 9	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.1059+79A>T		intron_variant	Intron 9 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75684 AN: 151300 Hom.: 20146 Cov.: 31

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.542

GnomAD2 exomes AF: 0.569 AC: 135224 AN: 237840 AF XY: 0.585

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.688

Gnomad EAS exome AF: 0.533

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.576 AC: 614298 AN: 1066902 Hom.: 179933 Cov.: 14 AF XY: 0.585 AC XY: 320295 AN XY: 547820

African (AFR) AF: 0.306 AC: 7724 AN: 25272

American (AMR) AF: 0.482 AC: 20925 AN: 43404

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 16123 AN: 23570

East Asian (EAS) AF: 0.606 AC: 22635 AN: 37372

South Asian (SAS) AF: 0.758 AC: 59308 AN: 78274

European-Finnish (FIN) AF: 0.582 AC: 29806 AN: 51212

Middle Eastern (MID) AF: 0.702 AC: 3513 AN: 5006

European-Non Finnish (NFE) AF: 0.566 AC: 427680 AN: 755646

Other (OTH) AF: 0.564 AC: 26584 AN: 47146

GnomAD4 genome AF: 0.500 AC: 75692 AN: 151418 Hom.: 20146 Cov.: 31 AF XY: 0.503 AC XY: 37215 AN XY: 73936

African (AFR) AF: 0.311 AC: 12856 AN: 41362

American (AMR) AF: 0.505 AC: 7660 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2385 AN: 3454

East Asian (EAS) AF: 0.546 AC: 2788 AN: 5102

South Asian (SAS) AF: 0.760 AC: 3659 AN: 4816

European-Finnish (FIN) AF: 0.580 AC: 6071 AN: 10462

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.567 AC: 38405 AN: 67758

Other (OTH) AF: 0.544 AC: 1139 AN: 2094

Alfa AF: 0.497 Hom.: 2830

Bravo AF: 0.481

Asia WGS AF: 0.622 AC: 2161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.69
PhyloP100		-0.35
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: rs10938435; hg19: chr4-46263864;