rs496650

Variant names:

• chr4-46262368-C-A
• rs496650
• NM_000807.4:c.857-240G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000807.4(GABRA2):​c.857-240G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 151,788 control chromosomes in the GnomAD database, including 20,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (20373 hom., cov: 32)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.113
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-46262368-C-A is Benign according to our data. Variant chr4-46262368-C-A is described in ClinVar as [Benign]. Clinvar id is 1239468.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.857-240G>T		intron_variant	Intron 8 of 9	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.857-240G>T		intron_variant	Intron 8 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76111 AN: 151670 Hom.: 20373 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.542

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

GnomAD4 genome AF: 0.501 AC: 76119 AN: 151788 Hom.: 20373 Cov.: 32 AF XY: 0.505 AC XY: 37472 AN XY: 74156

African (AFR) AF: 0.311 AC: 12889 AN: 41410

American (AMR) AF: 0.506 AC: 7709 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2398 AN: 3464

East Asian (EAS) AF: 0.549 AC: 2805 AN: 5112

South Asian (SAS) AF: 0.761 AC: 3667 AN: 4820

European-Finnish (FIN) AF: 0.586 AC: 6173 AN: 10526

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38593 AN: 67926

Other (OTH) AF: 0.543 AC: 1142 AN: 2102

Alfa AF: 0.513 Hom.: 2695

Bravo AF: 0.481

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.51
PhyloP100		-0.11
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: rs496650; hg19: chr4-46264385;