rs540363

Variant names:

• chr4-46272229-G-A
• rs540363
• NM_000807.4:c.857-10101C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-46272229-G-A
• chr4-46272229-G-C
• chr4-46272229-G-T

Variant summary

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

The NM_001330690.2(GABRA2):​c.857-10101C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,478 control chromosomes in the GnomAD database, including 20,344 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 0.50 (20344 hom., cov: 31)
• Consequence: GABRA2 NM_001330690.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.908
• Publications: 2 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 = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330690.2. 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.857-10101C>T		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.857-10101C>T		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.857-10101C>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.857-10101C>T		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.857-10101C>T		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507069.5	TSL:3	c.857-10101C>T		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75985 AN: 151360 Hom.: 20344 Cov.: 31

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.543

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

GnomAD4 genome AF: 0.502 AC: 75993 AN: 151478 Hom.: 20344 Cov.: 31 AF XY: 0.505 AC XY: 37382 AN XY: 73984

African (AFR) AF: 0.312 AC: 12896 AN: 41278

American (AMR) AF: 0.506 AC: 7672 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2401 AN: 3468

East Asian (EAS) AF: 0.549 AC: 2800 AN: 5104

South Asian (SAS) AF: 0.761 AC: 3660 AN: 4810

European-Finnish (FIN) AF: 0.585 AC: 6163 AN: 10530

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38510 AN: 67826

Other (OTH) AF: 0.544 AC: 1147 AN: 2108

Alfa AF: 0.504 Hom.: 3213

Bravo AF: 0.481

Asia WGS AF: 0.620 AC: 2153 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.28
DANN	Benign	0.26
PhyloP100		-0.91
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: rs540363; hg19: chr4-46274246;