rs140538607

chr5-161330976-G-A

Variant summary

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

The NM_001371727.1(GABRB2):c.984C>T(p.Tyr328=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GABRB2 NM_001371727.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.56

Genes affected

GABRB2 (HGNC:4082): (gamma-aminobutyric acid type A receptor subunit beta2) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-161330976-G-A is Benign according to our data. Variant chr5-161330976-G-A is described in ClinVar as [Benign]. Clinvar id is 388364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00123 (188/152292) while in subpopulation AFR AF= 0.00419 (174/41570). AF 95% confidence interval is 0.00368. There are 1 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB2	NM_001371727.1	c.984C>T	p.Tyr328=	synonymous_variant	8/10	ENST00000393959.6
GABRB2	NM_021911.3	c.984C>T	p.Tyr328=	synonymous_variant	9/11
GABRB2	NM_000813.3	c.984C>T	p.Tyr328=	synonymous_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB2	ENST00000393959.6	c.984C>T	p.Tyr328=	synonymous_variant	8/10	1	NM_001371727.1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000387 AC: 97 AN: 250630 Hom.: 0 AF XY: 0.000288 AC XY: 39 AN XY: 135596

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.000110 AC XY: 80 AN XY: 727244

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74456

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.00165

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GABRB2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2019

- -

Intellectual disability Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.5
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: rs140538607; hg19: chr5-160757983; COSMIC: COSV99195612;