chr4-46388848-C-G

Variant names:

• chr4-46388848-C-G
• rs11503014
• NM_000807.4:c.-10-132G>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.-10-132G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,437,656 control chromosomes in the GnomAD database, including 57,351 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 0.27 (5579 hom., cov: 32)
  • Exomes 𝑓: 0.28 (51772 hom.)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350
• Publications: 29 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.289 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.-10-132G>C		intron	N/A	NP_000798.2
	GABRA2	NM_001114175.3		c.-142G>C		5_prime_UTR	Exon 1 of 9	NP_001107647.1
	GABRA2	NM_001377151.1		c.-21G>C		5_prime_UTR	Exon 1 of 10	NP_001364080.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.-10-132G>C		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.-10-132G>C		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507460.1	TSL:1	c.-10-132G>C		intron	N/A	ENSP00000422805.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40824 AN: 151984 Hom.: 5569 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.284 AC: 364587 AN: 1285554 Hom.: 51772 Cov.: 30 AF XY: 0.282 AC XY: 176160 AN XY: 625176

African (AFR) AF: 0.298 AC: 8277 AN: 27786

American (AMR) AF: 0.239 AC: 4766 AN: 19942

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 4602 AN: 19082

East Asian (EAS) AF: 0.129 AC: 4211 AN: 32748

South Asian (SAS) AF: 0.181 AC: 10409 AN: 57472

European-Finnish (FIN) AF: 0.263 AC: 11892 AN: 45280

Middle Eastern (MID) AF: 0.275 AC: 1130 AN: 4116

European-Non Finnish (NFE) AF: 0.297 AC: 305171 AN: 1026198

Other (OTH) AF: 0.267 AC: 14129 AN: 52930

GnomAD4 genome AF: 0.269 AC: 40865 AN: 152102 Hom.: 5579 Cov.: 32 AF XY: 0.260 AC XY: 19298 AN XY: 74346

African (AFR) AF: 0.286 AC: 11865 AN: 41480

American (AMR) AF: 0.233 AC: 3557 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3468

East Asian (EAS) AF: 0.0883 AC: 456 AN: 5166

South Asian (SAS) AF: 0.158 AC: 764 AN: 4826

European-Finnish (FIN) AF: 0.246 AC: 2596 AN: 10572

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19889 AN: 67980

Other (OTH) AF: 0.283 AC: 598 AN: 2114

Alfa AF: 0.270 Hom.: 677

Bravo AF: 0.270

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.1
DANN	Benign	0.58
PhyloP100		-0.035
PromoterAI		0.020	Neutral
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: rs11503014; hg19: chr4-46390865;