4-46315942-T-C

Variant names:

• chr4-46315942-T-C
• rs279855
• NM_000807.4:c.256-3226A>G

Variant summary

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

The NM_000807.4(GABRA2):​c.256-3226A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 147,964 control chromosomes in the GnomAD database, including 11,310 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 0.38 (11310 hom., cov: 26)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• Publications: 1 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.256-3226A>G		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.256-3226A>G		intron_variant	Intron 4 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.383 AC: 56596 AN: 147858 Hom.: 11297 Cov.: 26

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.383 AC: 56626 AN: 147964 Hom.: 11310 Cov.: 26 AF XY: 0.383 AC XY: 27612 AN XY: 72110

African (AFR) AF: 0.266 AC: 10655 AN: 40066

American (AMR) AF: 0.452 AC: 6680 AN: 14768

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1047 AN: 3432

East Asian (EAS) AF: 0.517 AC: 2562 AN: 4952

South Asian (SAS) AF: 0.243 AC: 1138 AN: 4692

European-Finnish (FIN) AF: 0.415 AC: 4166 AN: 10050

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.437 AC: 29165 AN: 66776

Other (OTH) AF: 0.377 AC: 771 AN: 2044

Alfa AF: 0.408 Hom.: 1378

Bravo AF: 0.387

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.95
DANN	Benign	0.26
PhyloP100		-2.3
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: rs279855; hg19: chr4-46317959;