chr4-46245881-C-T

Variant names:

• chr4-46245881-C-T
• rs495818
• NM_000807.4:c.*4427G>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.*4427G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 150,812 control chromosomes in the GnomAD database, including 30,623 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 0.63 (30623 hom., cov: 31)
• Consequence: GABRA2 NM_000807.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.*4427G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.*4427G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.630 AC: 94965 AN: 150694 Hom.: 30580 Cov.: 31

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.632

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

GnomAD4 genome AF: 0.630 AC: 95052 AN: 150812 Hom.: 30623 Cov.: 31 AF XY: 0.631 AC XY: 46476 AN XY: 73658

African (AFR) AF: 0.750 AC: 30998 AN: 41358

American (AMR) AF: 0.556 AC: 8393 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2394 AN: 3446

East Asian (EAS) AF: 0.550 AC: 2795 AN: 5086

South Asian (SAS) AF: 0.779 AC: 3747 AN: 4810

European-Finnish (FIN) AF: 0.600 AC: 6308 AN: 10510

Middle Eastern (MID) AF: 0.653 AC: 188 AN: 288

European-Non Finnish (NFE) AF: 0.570 AC: 38342 AN: 67228

Other (OTH) AF: 0.633 AC: 1325 AN: 2094

Alfa AF: 0.594 Hom.: 3421

Bravo AF: 0.625

Asia WGS AF: 0.657 AC: 2278 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.75
DANN	Benign	0.30
PhyloP100		-0.16

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs495818; hg19: chr4-46247898;