4-46394181-A-T

Variant names:

• chr4-46394181-A-T
• rs1372472
• ENST00000510861.5:c.-10-5465T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000510861.5(GABRA2):​c.-10-5465T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 152,082 control chromosomes in the GnomAD database, including 7,026 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 0.27 (7026 hom., cov: 33)
• Consequence: GABRA2 ENST00000510861.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 2 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

ENSG00000249330 (HGNC:40247):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000510861.5	c.-10-5465T>A		intron_variant	Intron 1 of 9	5		ENSP00000421828.1
ENSG00000249330	ENST00000502455.2	n.438+3173A>T		intron_variant	Intron 2 of 2	4
ENSG00000249330	ENST00000651612.1	n.386+3173A>T		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41008 AN: 151964 Hom.: 7011 Cov.: 33

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.270 AC: 41033 AN: 152082 Hom.: 7026 Cov.: 33 AF XY: 0.281 AC XY: 20901 AN XY: 74344

African (AFR) AF: 0.0839 AC: 3484 AN: 41526

American (AMR) AF: 0.425 AC: 6492 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 838 AN: 3468

East Asian (EAS) AF: 0.655 AC: 3390 AN: 5172

South Asian (SAS) AF: 0.454 AC: 2192 AN: 4832

European-Finnish (FIN) AF: 0.344 AC: 3629 AN: 10562

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20276 AN: 67938

Other (OTH) AF: 0.278 AC: 588 AN: 2114

Alfa AF: 0.278 Hom.: 808

Bravo AF: 0.267

Asia WGS AF: 0.547 AC: 1896 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.026
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: rs1372472; hg19: chr4-46396198;