rs4695152

Variant names:

• chr4-46379640-C-G
• rs4695152
• NM_000807.4:c.187+6434G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000807.4(GABRA2):​c.187+6434G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 152,186 control chromosomes in the GnomAD database, including 101 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 0.029 (101 hom., cov: 32)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• 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=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0287 (4375/152186) while in subpopulation NFE AF = 0.0411 (2795/67996). AF 95% confidence interval is 0.0398. There are 101 homozygotes in GnomAd4. There are 2124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.187+6434G>C		intron_variant	Intron 3 of 9	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.187+6434G>C		intron_variant	Intron 3 of 9	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4368 AN: 152068 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.00922

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0229

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

GnomAD4 genome AF: 0.0287 AC: 4375 AN: 152186 Hom.: 101 Cov.: 32 AF XY: 0.0286 AC XY: 2124 AN XY: 74390

African (AFR) AF: 0.00920 AC: 382 AN: 41538

American (AMR) AF: 0.0150 AC: 229 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5170

South Asian (SAS) AF: 0.0328 AC: 158 AN: 4816

European-Finnish (FIN) AF: 0.0626 AC: 662 AN: 10578

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2795 AN: 67996

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0370 Hom.: 10

Bravo AF: 0.0229

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.23
DANN	Benign	0.69
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs4695152; hg19: chr4-46381657;