rs541418

Variant names:

• chr4-46251199-C-T
• rs541418
• NM_000807.4:c.1060-595G>A

Variant summary

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

The NM_000807.4(GABRA2):​c.1060-595G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 151,154 control chromosomes in the GnomAD database, including 28,596 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 0.61 (28596 hom., cov: 31)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29
• Publications: 1 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 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.1060-595G>A		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.1240-595G>A		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.1240-595G>A		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.1060-595G>A		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000507069.5	TSL:3	c.1240-595G>A		intron	N/A	ENSP00000427603.1
	GABRA2	ENST00000356504.5	TSL:2	c.1060-595G>A		intron	N/A	ENSP00000348897.1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92203 AN: 151036 Hom.: 28588 Cov.: 31

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.778

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.610 AC: 92234 AN: 151154 Hom.: 28596 Cov.: 31 AF XY: 0.611 AC XY: 45102 AN XY: 73842

African (AFR) AF: 0.683 AC: 28204 AN: 41324

American (AMR) AF: 0.546 AC: 8252 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2393 AN: 3448

East Asian (EAS) AF: 0.549 AC: 2782 AN: 5070

South Asian (SAS) AF: 0.778 AC: 3746 AN: 4812

European-Finnish (FIN) AF: 0.600 AC: 6326 AN: 10540

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38493 AN: 67560

Other (OTH) AF: 0.616 AC: 1289 AN: 2094

Alfa AF: 0.585 Hom.: 9416

Bravo AF: 0.603

Asia WGS AF: 0.645 AC: 2246 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.35
DANN	Benign	0.66
PhyloP100		-2.3
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: rs541418; hg19: chr4-46253216;