rs76812964

Positions:

• chr15-26567633-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000814.6(GABRB3):​c.783G>A​(p.Ser261=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,613,916 control chromosomes in the GnomAD database, including 854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (52 hom., cov: 33)
  • Exomes 𝑓: 0.030 (802 hom.)
• Consequence: GABRB3 NM_000814.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47

Genes affected

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-26567633-C-T is Benign according to our data. Variant chr15-26567633-C-T is described in ClinVar as [Benign]. Clinvar id is 256821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-26567633-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0225 (3430/152242) while in subpopulation NFE AF= 0.0325 (2210/68016). AF 95% confidence interval is 0.0314. There are 52 homozygotes in gnomad4. There are 1626 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3430 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.783G>A	p.Ser261=	synonymous_variant	7/9	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.783G>A	p.Ser261=	synonymous_variant	7/9	1	NM_000814.6	ENSP00000308725	P1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3427 AN: 152124 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.0247 AC: 6219 AN: 251310 Hom.: 113 AF XY: 0.0249 AC XY: 3384 AN XY: 135834

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00751

Gnomad FIN exome AF: 0.0367

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0305 AC: 44525 AN: 1461674 Hom.: 802 Cov.: 31 AF XY: 0.0297 AC XY: 21609 AN XY: 727136

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0470

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00670

Gnomad4 FIN exome AF: 0.0354

Gnomad4 NFE exome AF: 0.0344

Gnomad4 OTH exome AF: 0.0252

GnomAD4 genome AF: 0.0225 AC: 3430 AN: 152242 Hom.: 52 Cov.: 33 AF XY: 0.0218 AC XY: 1626 AN XY: 74424

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0307 Hom.: 44

Bravo AF: 0.0213

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0320

EpiControl AF: 0.0334

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Seizure Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2016

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.54
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs76812964; hg19: chr15-26812780;