chr4-46327706-T-A

Variant names:

• chr4-46327706-T-A
• rs279845
• NM_000807.4:c.255+4909A>T

Variant summary

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

The NM_000807.4(GABRA2):​c.255+4909A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,836 control chromosomes in the GnomAD database, including 13,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.41 (13182 hom., cov: 32)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 0.306
• Publications: 31 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000807.4. 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.255+4909A>T		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.255+4909A>T		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.255+4909A>T		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.255+4909A>T		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.255+4909A>T		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507069.5	TSL:3	c.255+4909A>T		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61959 AN: 151720 Hom.: 13166 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.408 AC: 62005 AN: 151836 Hom.: 13182 Cov.: 32 AF XY: 0.411 AC XY: 30506 AN XY: 74184

African (AFR) AF: 0.295 AC: 12239 AN: 41436

American (AMR) AF: 0.468 AC: 7127 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1115 AN: 3466

East Asian (EAS) AF: 0.560 AC: 2875 AN: 5132

South Asian (SAS) AF: 0.319 AC: 1537 AN: 4822

European-Finnish (FIN) AF: 0.470 AC: 4965 AN: 10554

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30861 AN: 67892

Other (OTH) AF: 0.393 AC: 829 AN: 2110

Alfa AF: 0.446 Hom.: 8596

Bravo AF: 0.408

Asia WGS AF: 0.425 AC: 1475 AN: 3476

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alcoholism, susceptibility to Other:1

Apr 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.77
PhyloP100		0.31
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: rs279845; hg19: chr4-46329723;