4-46272434-T-C

Variant names:

• chr4-46272434-T-C
• rs519270
• NM_000807.4:c.857-10306A>G

Variant summary

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

The ENST00000381620.9(GABRA2):​c.857-10306A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 151,780 control chromosomes in the GnomAD database, including 22,650 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 0.54 (22650 hom., cov: 32)
• Consequence: GABRA2 ENST00000381620.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.678
• 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

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 (SAS) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381620.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	NM_000807.4	MANE Select	c.857-10306A>G		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.857-10306A>G		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.857-10306A>G		intron	N/A	NP_001364073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.857-10306A>G		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.857-10306A>G		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507069.5	TSL:3	c.857-10306A>G		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81957 AN: 151662 Hom.: 22626 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.540 AC: 82018 AN: 151780 Hom.: 22650 Cov.: 32 AF XY: 0.543 AC XY: 40297 AN XY: 74170

African (AFR) AF: 0.447 AC: 18517 AN: 41388

American (AMR) AF: 0.519 AC: 7891 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2411 AN: 3472

East Asian (EAS) AF: 0.548 AC: 2819 AN: 5142

South Asian (SAS) AF: 0.762 AC: 3665 AN: 4812

European-Finnish (FIN) AF: 0.585 AC: 6175 AN: 10554

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38585 AN: 67904

Other (OTH) AF: 0.571 AC: 1208 AN: 2114

Alfa AF: 0.410 Hom.: 1175

Bravo AF: 0.525

Asia WGS AF: 0.639 AC: 2222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.92
DANN	Benign	0.69
PhyloP100		-0.68
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: rs519270; hg19: chr4-46274451;