rs140682

Variant names:

• chr15-26937210-T-C
• rs140682
• NM_000810.4:c.606T>C

Variant summary

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

The NM_000810.4(GABRA5):​c.606T>C​(p.Val202Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,613,496 control chromosomes in the GnomAD database, including 281,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31586 hom., cov: 33)
  • Exomes 𝑓: 0.58 (250053 hom.)
• Consequence: GABRA5 NM_000810.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.209
• Publications: 23 publications found

Genes affected

GABRA5 (HGNC:4079): (gamma-aminobutyric acid type A receptor subunit alpha5) 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. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  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=-0.61).
• BP6: Variant 15-26937210-T-C is Benign according to our data. Variant chr15-26937210-T-C is described in ClinVar as Benign. ClinVar VariationId is 1285288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.209 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000810.4. 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
	GABRA5	NM_000810.4	MANE Select	c.606T>C	p.Val202Val	synonymous	Exon 8 of 11	NP_000801.1
	GABRA5	NM_001165037.2		c.606T>C	p.Val202Val	synonymous	Exon 8 of 11	NP_001158509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA5	ENST00000335625.10	TSL:1 MANE Select	c.606T>C	p.Val202Val	synonymous	Exon 8 of 11	ENSP00000335592.5
	GABRB3	ENST00000541819.6	TSL:1	c.200+2027A>G		intron	N/A	ENSP00000442408.2
	GABRA5	ENST00000355395.9	TSL:5	c.606T>C	p.Val202Val	synonymous	Exon 7 of 10	ENSP00000347557.5

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96402 AN: 152012 Hom.: 31530 Cov.: 33

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.596

GnomAD2 exomes AF: 0.586 AC: 145971 AN: 249264 AF XY: 0.583

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.486

Gnomad EAS exome AF: 0.660

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.582 AC: 850623 AN: 1461366 Hom.: 250053 Cov.: 49 AF XY: 0.581 AC XY: 422368 AN XY: 726996

African (AFR) AF: 0.817 AC: 27343 AN: 33476

American (AMR) AF: 0.501 AC: 22385 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 12735 AN: 26132

East Asian (EAS) AF: 0.680 AC: 26979 AN: 39696

South Asian (SAS) AF: 0.585 AC: 50434 AN: 86238

European-Finnish (FIN) AF: 0.648 AC: 34628 AN: 53398

Middle Eastern (MID) AF: 0.475 AC: 2739 AN: 5766

European-Non Finnish (NFE) AF: 0.574 AC: 638424 AN: 1111582

Other (OTH) AF: 0.579 AC: 34956 AN: 60356

GnomAD4 genome AF: 0.634 AC: 96512 AN: 152130 Hom.: 31586 Cov.: 33 AF XY: 0.634 AC XY: 47177 AN XY: 74374

African (AFR) AF: 0.803 AC: 33316 AN: 41514

American (AMR) AF: 0.534 AC: 8158 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1674 AN: 3470

East Asian (EAS) AF: 0.676 AC: 3485 AN: 5158

South Asian (SAS) AF: 0.593 AC: 2860 AN: 4822

European-Finnish (FIN) AF: 0.657 AC: 6965 AN: 10600

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38090 AN: 67976

Other (OTH) AF: 0.592 AC: 1247 AN: 2106

Alfa AF: 0.596 Hom.: 19104

Bravo AF: 0.636

Asia WGS AF: 0.632 AC: 2200 AN: 3478

EpiCase AF: 0.552

EpiControl AF: 0.560

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 79 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		0.21
Mutation Taster		=98/2	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: rs140682; hg19: chr15-27182357; COSMIC: COSV59484940; COSMIC: COSV59484940;