NM_000807.4:c.559+743A>G

Variant names:

• chr4-46309430-T-C
• rs1808851
• NM_000807.4:c.559+743A>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.559+743A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 151,646 control chromosomes in the GnomAD database, including 12,224 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 0.39 (12224 hom., cov: 31)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.408
• 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=-0.57).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.559+743A>G		intron_variant	Intron 6 of 9	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.559+743A>G		intron_variant	Intron 6 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59733 AN: 151526 Hom.: 12204 Cov.: 31

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.394 AC: 59789 AN: 151646 Hom.: 12224 Cov.: 31 AF XY: 0.395 AC XY: 29227 AN XY: 74084

African (AFR) AF: 0.308 AC: 12729 AN: 41358

American (AMR) AF: 0.453 AC: 6890 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3464

East Asian (EAS) AF: 0.523 AC: 2666 AN: 5096

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4806

European-Finnish (FIN) AF: 0.416 AC: 4376 AN: 10514

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29645 AN: 67900

Other (OTH) AF: 0.381 AC: 803 AN: 2106

Alfa AF: 0.420 Hom.: 56995

Bravo AF: 0.400

Asia WGS AF: 0.376 AC: 1306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.8
DANN	Benign	0.56
PhyloP100		0.41
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: rs1808851; hg19: chr4-46311447;