4-46254540-A-T

Variant names:

• chr4-46254540-A-T
• rs693547
• NM_000807.4:c.1060-3936T>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.1060-3936T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 151,090 control chromosomes in the GnomAD database, including 30,070 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 0.62 (30070 hom., cov: 30)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.358
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.742 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.1060-3936T>A		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.1239+1655T>A		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.1239+1655T>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.1060-3936T>A		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000507069.5	TSL:3	c.1239+1655T>A		intron	N/A	ENSP00000427603.1
	GABRA2	ENST00000356504.5	TSL:2	c.1060-3936T>A		intron	N/A	ENSP00000348897.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94092 AN: 150972 Hom.: 30029 Cov.: 30

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.629

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

GnomAD4 genome AF: 0.623 AC: 94176 AN: 151090 Hom.: 30070 Cov.: 30 AF XY: 0.623 AC XY: 45933 AN XY: 73774

African (AFR) AF: 0.749 AC: 30934 AN: 41294

American (AMR) AF: 0.551 AC: 8309 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2394 AN: 3454

East Asian (EAS) AF: 0.548 AC: 2797 AN: 5100

South Asian (SAS) AF: 0.758 AC: 3646 AN: 4810

European-Finnish (FIN) AF: 0.571 AC: 6015 AN: 10540

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38014 AN: 67518

Other (OTH) AF: 0.630 AC: 1317 AN: 2092

Alfa AF: 0.428 Hom.: 1054

Bravo AF: 0.621

Asia WGS AF: 0.652 AC: 2269 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.60
DANN	Benign	0.49
PhyloP100		-0.36
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: rs693547; hg19: chr4-46256557;