chr4-46391595-T-A

Variant names:

• chr4-46391595-T-A
• rs894269
• ENST00000510861.5:c.-10-2879A>T

Variant summary

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

The ENST00000510861.5(GABRA2):​c.-10-2879A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 152,220 control chromosomes in the GnomAD database, including 217 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 0.048 (217 hom., cov: 33)
• Consequence: GABRA2 ENST00000510861.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 6 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

ENSG00000249330 (HGNC:40247):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000510861.5	c.-10-2879A>T		intron_variant	Intron 1 of 9	5		ENSP00000421828.1
ENSG00000249330	ENST00000502455.2	n.438+587T>A		intron_variant	Intron 2 of 2	4
ENSG00000249330	ENST00000651612.1	n.386+587T>A		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7357 AN: 152102 Hom.: 218 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0926

Gnomad FIN AF: 0.0477

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0627

Gnomad OTH AF: 0.0511

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0483 AC: 7354 AN: 152220 Hom.: 217 Cov.: 33 AF XY: 0.0476 AC XY: 3540 AN XY: 74412

African (AFR) AF: 0.0213 AC: 886 AN: 41542

American (AMR) AF: 0.0403 AC: 617 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.0266 AC: 137 AN: 5160

South Asian (SAS) AF: 0.0925 AC: 446 AN: 4824

European-Finnish (FIN) AF: 0.0477 AC: 506 AN: 10598

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0627 AC: 4264 AN: 68016

Other (OTH) AF: 0.0506 AC: 107 AN: 2114

Alfa AF: 0.00181 Hom.: 61052

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.1
DANN	Benign	0.61
PhyloP100		-0.13
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: rs894269; hg19: chr4-46393612;