NM_000807.4:c.188-3T>C

Variant names:

• chr4-46332685-A-G
• rs279827
• NM_000807.4:c.188-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000807.4(GABRA2):​c.188-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,516,768 control chromosomes in the GnomAD database, including 148,881 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13516 hom., cov: 32)
  • Exomes 𝑓: 0.44 (135365 hom.)
• Consequence: GABRA2 NM_000807.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001221
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.75
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-46332685-A-G is Benign according to our data. Variant chr4-46332685-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 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.188-3T>C		splice_region intron	N/A	NP_000798.2	P47869-1
	GABRA2	NM_001330690.2		c.188-3T>C		splice_region intron	N/A	NP_001317619.1	E9PBQ7
	GABRA2	NM_001377144.1		c.188-3T>C		splice_region intron	N/A	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.188-3T>C		splice_region intron	N/A	ENSP00000371033.4	P47869-1
	GABRA2	ENST00000515082.5	TSL:1	c.188-3T>C		splice_region intron	N/A	ENSP00000423840.1	G5E9Z6
	GABRA2	ENST00000507069.5	TSL:3	c.188-3T>C		splice_region intron	N/A	ENSP00000427603.1	E9PBQ7

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62955 AN: 151810 Hom.: 13497 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.398

GnomAD2 exomes AF: 0.437 AC: 108330 AN: 247996 AF XY: 0.429

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.565

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.440 AC: 600608 AN: 1364842 Hom.: 135365 Cov.: 21 AF XY: 0.436 AC XY: 298136 AN XY: 684556

African (AFR) AF: 0.296 AC: 9372 AN: 31644

American (AMR) AF: 0.510 AC: 22464 AN: 44074

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8408 AN: 25470

East Asian (EAS) AF: 0.520 AC: 20261 AN: 38960

South Asian (SAS) AF: 0.306 AC: 25678 AN: 83860

European-Finnish (FIN) AF: 0.475 AC: 25189 AN: 53068

Middle Eastern (MID) AF: 0.292 AC: 1606 AN: 5506

European-Non Finnish (NFE) AF: 0.451 AC: 462824 AN: 1025266

Other (OTH) AF: 0.435 AC: 24806 AN: 56994

GnomAD4 genome AF: 0.415 AC: 63010 AN: 151926 Hom.: 13516 Cov.: 32 AF XY: 0.417 AC XY: 30982 AN XY: 74226

African (AFR) AF: 0.314 AC: 13032 AN: 41464

American (AMR) AF: 0.470 AC: 7163 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1116 AN: 3468

East Asian (EAS) AF: 0.561 AC: 2889 AN: 5150

South Asian (SAS) AF: 0.319 AC: 1536 AN: 4820

European-Finnish (FIN) AF: 0.471 AC: 4961 AN: 10544

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31017 AN: 67940

Other (OTH) AF: 0.397 AC: 837 AN: 2110

Alfa AF: 0.435 Hom.: 11282

Bravo AF: 0.415

Asia WGS AF: 0.430 AC: 1493 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GABRA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.90
PhyloP100		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.090		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: rs279827; hg19: chr4-46334702; COSMIC: COSV62919922;