4-46323187-C-T

Variant names:

• chr4-46323187-C-T
• rs279843
• NM_000807.4:c.255+9428G>A

Variant summary

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

The NM_000807.4(GABRA2):​c.255+9428G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,602 control chromosomes in the GnomAD database, including 14,868 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 0.44 (14868 hom., cov: 31)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 9 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.255+9428G>A		intron_variant	Intron 4 of 9	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.255+9428G>A		intron_variant	Intron 4 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66568 AN: 151484 Hom.: 14840 Cov.: 31

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.440 AC: 66632 AN: 151602 Hom.: 14868 Cov.: 31 AF XY: 0.438 AC XY: 32466 AN XY: 74042

African (AFR) AF: 0.456 AC: 18882 AN: 41402

American (AMR) AF: 0.475 AC: 7214 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1062 AN: 3464

East Asian (EAS) AF: 0.547 AC: 2796 AN: 5108

South Asian (SAS) AF: 0.270 AC: 1300 AN: 4810

European-Finnish (FIN) AF: 0.416 AC: 4374 AN: 10526

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29696 AN: 67802

Other (OTH) AF: 0.406 AC: 855 AN: 2104

Alfa AF: 0.387 Hom.: 2092

Bravo AF: 0.450

Asia WGS AF: 0.413 AC: 1435 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.75
DANN	Benign	0.57
PhyloP100		-1.2
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: rs279843; hg19: chr4-46325204;