NM_000807.4:c.477-1053C>G

Variant names:

• chr4-46311308-G-C
• rs279861
• NM_000807.4:c.477-1053C>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.477-1053C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 151,990 control chromosomes in the GnomAD database, including 11,562 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 (11562 hom., cov: 33)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.477-1053C>G		intron_variant	Intron 5 of 9	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.477-1053C>G		intron_variant	Intron 5 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57455 AN: 151874 Hom.: 11547 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.374

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

GnomAD4 genome AF: 0.378 AC: 57487 AN: 151990 Hom.: 11562 Cov.: 33 AF XY: 0.379 AC XY: 28128 AN XY: 74280

African (AFR) AF: 0.252 AC: 10461 AN: 41454

American (AMR) AF: 0.449 AC: 6863 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1057 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2687 AN: 5158

South Asian (SAS) AF: 0.241 AC: 1162 AN: 4814

European-Finnish (FIN) AF: 0.415 AC: 4386 AN: 10560

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

European-Non Finnish (NFE) AF: 0.436 AC: 29633 AN: 67942

Other (OTH) AF: 0.374 AC: 786 AN: 2104

Alfa AF: 0.408 Hom.: 1642

Bravo AF: 0.382

Asia WGS AF: 0.368 AC: 1276 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.79
PhyloP100		-0.23
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: rs279861; hg19: chr4-46313325;