rs2229944

Positions:

• chr5-161294312-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001371727.1(GABRB2):​c.1308C>T​(p.Ala436=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,614,038 control chromosomes in the GnomAD database, including 7,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1112 hom., cov: 32)
  • Exomes 𝑓: 0.083 (6622 hom.)
• Consequence: GABRB2 NM_001371727.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.17

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=-0.51).
• BP6: Variant 5-161294312-G-A is Benign according to our data. Variant chr5-161294312-G-A is described in ClinVar as [Benign]. Clinvar id is 380805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRB2	NM_001371727.1	c.1308C>T	p.Ala436=	synonymous_variant	10/10	ENST00000393959.6	NP_001358656.1
GABRB2	NM_021911.3	c.1308C>T	p.Ala436=	synonymous_variant	11/11		NP_068711.1
GABRB2	NM_000813.3	c.1194C>T	p.Ala398=	synonymous_variant	10/10		NP_000804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB2	ENST00000393959.6	c.1308C>T	p.Ala436=	synonymous_variant	10/10	1	NM_001371727.1	ENSP00000377531

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16818 AN: 152092 Hom.: 1109 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.0837

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0757

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.114 AC: 28696 AN: 251182 Hom.: 2427 AF XY: 0.107 AC XY: 14497 AN XY: 135720

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.0889

Gnomad EAS exome AF: 0.0387

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.0917

Gnomad NFE exome AF: 0.0769

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.0834 AC: 121979 AN: 1461828 Hom.: 6622 Cov.: 31 AF XY: 0.0834 AC XY: 60629 AN XY: 727216

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.0881

Gnomad4 EAS exome AF: 0.0298

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.0913

Gnomad4 NFE exome AF: 0.0715

Gnomad4 OTH exome AF: 0.0959

GnomAD4 genome AF: 0.111 AC: 16839 AN: 152210 Hom.: 1112 Cov.: 32 AF XY: 0.112 AC XY: 8355 AN XY: 74420

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.0837

Gnomad4 EAS AF: 0.0379

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0861

Gnomad4 NFE AF: 0.0757

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0909 Hom.: 980

Bravo AF: 0.122

Asia WGS AF: 0.102 AC: 355 AN: 3478

EpiCase AF: 0.0843

EpiControl AF: 0.0817

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 40. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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	Athena Diagnostics	Jun 29, 2017	- -

Intellectual disability Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.7
DANN	Benign	0.70

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: rs2229944; hg19: chr5-160721319; COSMIC: COSV50955269;