chr4-46389556-T-A

Variant names:

• chr4-46389556-T-A
• rs2119767
• NM_000807.4:c.-11+179A>T

Variant summary

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

The NM_000807.4(GABRA2):​c.-11+179A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 408,946 control chromosomes in the GnomAD database, including 17,565 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 (6710 hom., cov: 29)
  • Exomes 𝑓: 0.28 (10855 hom.)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.494
• Publications: 11 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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 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.-11+179A>T		intron	N/A	NP_000798.2
	GABRA2	NM_001377144.1		c.-11+179A>T		intron	N/A	NP_001364073.1
	GABRA2	NM_001377145.1		c.-11+706A>T		intron	N/A	NP_001364074.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.-11+179A>T		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.-11+706A>T		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000510861.5	TSL:5	c.-10-840A>T		intron	N/A	ENSP00000421828.1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41038 AN: 151448 Hom.: 6695 Cov.: 29

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0980

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.278 AC: 71543 AN: 257380 Hom.: 10855 Cov.: 5 AF XY: 0.277 AC XY: 33779 AN XY: 122120

African (AFR) AF: 0.0892 AC: 445 AN: 4986

American (AMR) AF: 0.460 AC: 126 AN: 274

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 352 AN: 1560

East Asian (EAS) AF: 0.636 AC: 611 AN: 960

South Asian (SAS) AF: 0.400 AC: 2023 AN: 5052

European-Finnish (FIN) AF: 0.275 AC: 22 AN: 80

Middle Eastern (MID) AF: 0.214 AC: 113 AN: 528

European-Non Finnish (NFE) AF: 0.277 AC: 65394 AN: 235660

Other (OTH) AF: 0.297 AC: 2457 AN: 8280

GnomAD4 genome AF: 0.271 AC: 41065 AN: 151566 Hom.: 6710 Cov.: 29 AF XY: 0.281 AC XY: 20809 AN XY: 73978

African (AFR) AF: 0.124 AC: 5141 AN: 41328

American (AMR) AF: 0.424 AC: 6456 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 818 AN: 3464

East Asian (EAS) AF: 0.658 AC: 3324 AN: 5054

South Asian (SAS) AF: 0.454 AC: 2182 AN: 4802

European-Finnish (FIN) AF: 0.310 AC: 3247 AN: 10472

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19167 AN: 67910

Other (OTH) AF: 0.279 AC: 588 AN: 2104

Alfa AF: 0.263 Hom.: 767

Bravo AF: 0.274

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		0.49
PromoterAI		-0.018	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: rs2119767; hg19: chr4-46391573;