5-161330900-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001371727.1(GABRB2):c.1060C>A(p.Arg354Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R354H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.80

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRB2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB2	NM_001371727.1	c.1060C>A	p.Arg354Ser	missense_variant	8/10	ENST00000393959.6
GABRB2	NM_021911.3	c.1060C>A	p.Arg354Ser	missense_variant	9/11
GABRB2	NM_000813.3	c.1060C>A	p.Arg354Ser	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB2	ENST00000393959.6	c.1060C>A	p.Arg354Ser	missense_variant	8/10	1	NM_001371727.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249376 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GABRB2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

The GABRB2 c.1060C>A variant is predicted to result in the amino acid substitution p.Arg354Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-160757907-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1347808). This variant has not been reported in the literature in individuals affected with GABRB2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 354 of the GABRB2 protein (p.Arg354Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;T;.;T;.
Eigen	Benign	0.078
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.1	L;L;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.055	T;T;T;T;T;T;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T
Polyphen		0.60	P;P;B;B;B;B;.
Vest4		0.67
MutPred		0.56		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);.;Gain of loop (P = 0.0045);.;.;
MVP		0.99
MPC		0.45
ClinPred		0.46	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.87

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: rs41298406; hg19: chr5-160757907; COSMIC: COSV50963602;