chr4-46391595-T-C

Variant names:

• chr4-46391595-T-C
• rs894269
• ENST00000510861.5:c.-10-2879A>G

Variant summary

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

The ENST00000502455.2(ENSG00000249330):​n.438+587T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 152,184 control chromosomes in the GnomAD database, including 53,738 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 0.84 (53738 hom., cov: 33)
• Consequence: ENSG00000249330 ENST00000502455.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 6 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, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000502455.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000510861.5	TSL:5	c.-10-2879A>G		intron	N/A	ENSP00000421828.1	P47869-1
	ENSG00000249330	ENST00000502455.2	TSL:4	n.438+587T>C		intron	N/A
	ENSG00000249330	ENST00000651612.1		n.386+587T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127429 AN: 152066 Hom.: 53675 Cov.: 33

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.825

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

GnomAD4 genome AF: 0.838 AC: 127554 AN: 152184 Hom.: 53738 Cov.: 33 AF XY: 0.841 AC XY: 62544 AN XY: 74390

African (AFR) AF: 0.931 AC: 38652 AN: 41538

American (AMR) AF: 0.828 AC: 12667 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2789 AN: 3472

East Asian (EAS) AF: 0.852 AC: 4397 AN: 5158

South Asian (SAS) AF: 0.769 AC: 3706 AN: 4818

European-Finnish (FIN) AF: 0.850 AC: 9005 AN: 10590

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53665 AN: 68004

Other (OTH) AF: 0.826 AC: 1745 AN: 2112

Alfa AF: 0.804 Hom.: 61052

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.65
PhyloP100		-0.13
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs894269;

hg19: chr4-46393612;