4-46398314-A-G

Variant names:

• chr4-46398314-A-G
• rs1025852
• ENST00000510861.5:c.-10-9598T>C

Variant summary

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

The ENST00000510861.5(GABRA2):​c.-10-9598T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 152,042 control chromosomes in the GnomAD database, including 30,032 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 (30032 hom., cov: 32)
• Consequence: GABRA2 ENST00000510861.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 5 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:):

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 (EAS) allele frequency at 95% confidence interval = 0.719 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.-10-9598T>C		intron_variant	Intron 1 of 9	5		ENSP00000421828.1
ENSG00000249330	ENST00000502455.2	n.438+7306A>G		intron_variant	Intron 2 of 2	4
ENSG00000249330	ENST00000651612.1	n.386+7306A>G		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95330 AN: 151924 Hom.: 29993 Cov.: 32

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.620

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

GnomAD4 genome AF: 0.628 AC: 95426 AN: 152042 Hom.: 30032 Cov.: 32 AF XY: 0.628 AC XY: 46679 AN XY: 74314

African (AFR) AF: 0.580 AC: 24040 AN: 41466

American (AMR) AF: 0.691 AC: 10550 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1906 AN: 3470

East Asian (EAS) AF: 0.738 AC: 3817 AN: 5170

South Asian (SAS) AF: 0.634 AC: 3057 AN: 4820

European-Finnish (FIN) AF: 0.623 AC: 6592 AN: 10584

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43392 AN: 67944

Other (OTH) AF: 0.623 AC: 1316 AN: 2114

Alfa AF: 0.631 Hom.: 51433

Bravo AF: 0.633

Asia WGS AF: 0.706 AC: 2452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.50
DANN	Benign	0.45
PhyloP100		-1.0
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: rs1025852; hg19: chr4-46400331;