chr4-46312576-T-C

Variant names:

• chr4-46312576-T-C
• rs279858
• NM_000807.4:c.396A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000807.4(GABRA2):​c.396A>G​(p.Lys132Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,595,942 control chromosomes in the GnomAD database, including 145,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11580 hom., cov: 32)
  • Exomes 𝑓: 0.43 (133934 hom.)
• Consequence: GABRA2 NM_000807.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.110
• Publications: 123 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, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-46312576-T-C is Benign according to our data. Variant chr4-46312576-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	NM_000807.4	MANE Select	c.396A>G	p.Lys132Lys	synonymous	Exon 5 of 10	NP_000798.2	P47869-1
	GABRA2	NM_001330690.2		c.396A>G	p.Lys132Lys	synonymous	Exon 5 of 11	NP_001317619.1	E9PBQ7
	GABRA2	NM_001377144.1		c.396A>G	p.Lys132Lys	synonymous	Exon 5 of 11	NP_001364073.1	E9PBQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.396A>G	p.Lys132Lys	synonymous	Exon 5 of 10	ENSP00000371033.4	P47869-1
	GABRA2	ENST00000515082.5	TSL:1	c.396A>G	p.Lys132Lys	synonymous	Exon 5 of 9	ENSP00000423840.1	G5E9Z6
	GABRA2	ENST00000507069.5	TSL:3	c.396A>G	p.Lys132Lys	synonymous	Exon 4 of 10	ENSP00000427603.1	E9PBQ7

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57479 AN: 151908 Hom.: 11565 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.404 AC: 95718 AN: 237012 AF XY: 0.397

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.518

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.425 AC: 613714 AN: 1443916 Hom.: 133934 Cov.: 31 AF XY: 0.419 AC XY: 300932 AN XY: 718114

African (AFR) AF: 0.239 AC: 7764 AN: 32530

American (AMR) AF: 0.492 AC: 20160 AN: 41004

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 7947 AN: 25426

East Asian (EAS) AF: 0.486 AC: 19029 AN: 39136

South Asian (SAS) AF: 0.242 AC: 20167 AN: 83174

European-Finnish (FIN) AF: 0.418 AC: 22220 AN: 53160

Middle Eastern (MID) AF: 0.275 AC: 1563 AN: 5674

European-Non Finnish (NFE) AF: 0.444 AC: 490409 AN: 1104286

Other (OTH) AF: 0.411 AC: 24455 AN: 59526

GnomAD4 genome AF: 0.378 AC: 57511 AN: 152026 Hom.: 11580 Cov.: 32 AF XY: 0.379 AC XY: 28136 AN XY: 74302

African (AFR) AF: 0.252 AC: 10480 AN: 41510

American (AMR) AF: 0.449 AC: 6849 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1056 AN: 3466

East Asian (EAS) AF: 0.524 AC: 2701 AN: 5154

South Asian (SAS) AF: 0.241 AC: 1162 AN: 4826

European-Finnish (FIN) AF: 0.415 AC: 4383 AN: 10572

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.436 AC: 29644 AN: 67936

Other (OTH) AF: 0.372 AC: 784 AN: 2106

Alfa AF: 0.377 Hom.: 8250

Bravo AF: 0.383

Asia WGS AF: 0.368 AC: 1279 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GABRA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.7
DANN	Benign	0.63
PhyloP100		-0.11
Mutation Taster		=95/5	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: rs279858; hg19: chr4-46314593; COSMIC: COSV62914124;