chr4-46370913-C-G

Variant names:

• chr4-46370913-C-G
• rs10024869
• NM_000807.4:c.187+15161G>C

Variant summary

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

The NM_000807.4(GABRA2):​c.187+15161G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 151,948 control chromosomes in the GnomAD database, including 4,135 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 0.23 (4135 hom., cov: 32)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 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.187+15161G>C		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.187+15161G>C		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.187+15161G>C		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.187+15161G>C		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.187+15161G>C		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507460.1	TSL:1	c.188-1907G>C		intron	N/A	ENSP00000422805.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34461 AN: 151830 Hom.: 4128 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.0819

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.227 AC: 34480 AN: 151948 Hom.: 4135 Cov.: 32 AF XY: 0.218 AC XY: 16180 AN XY: 74244

African (AFR) AF: 0.236 AC: 9772 AN: 41446

American (AMR) AF: 0.192 AC: 2921 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3468

East Asian (EAS) AF: 0.0567 AC: 293 AN: 5168

South Asian (SAS) AF: 0.0820 AC: 395 AN: 4818

European-Finnish (FIN) AF: 0.188 AC: 1986 AN: 10548

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17435 AN: 67950

Other (OTH) AF: 0.232 AC: 488 AN: 2104

Alfa AF: 0.112 Hom.: 180

Bravo AF: 0.233

Asia WGS AF: 0.0850 AC: 294 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	0.25
DANN	Benign	0.38
PhyloP100		-1.8
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: rs10024869; hg19: chr4-46372930;