rs1085307993

Variant names:

• chr5-161331056-C-T
• rs1085307993
• NM_001371727.1:c.904G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001371727.1(GABRB2):​c.904G>A​(p.Val302Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GABRB2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 3.3968 (above the threshold of 3.09). Trascript score misZ: 4.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to undetermined early-onset epileptic encephalopathy, epileptic encephalopathy, infantile or early childhood, 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 5-161331056-C-T is Pathogenic according to our data. Variant chr5-161331056-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-161331056-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB2	NM_001371727.1	c.904G>A	p.Val302Met	missense_variant	Exon 8 of 10	ENST00000393959.6	NP_001358656.1
GABRB2	NM_021911.3	c.904G>A	p.Val302Met	missense_variant	Exon 9 of 11		NP_068711.1
GABRB2	NM_000813.3	c.904G>A	p.Val302Met	missense_variant	Exon 9 of 10		NP_000804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB2	ENST00000393959.6	c.904G>A	p.Val302Met	missense_variant	Exon 8 of 10	1	NM_001371727.1	ENSP00000377531.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jul 31, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V302M variant in the GABRB2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The V302M variant is not observed in large population cohorts (Lek et al., 2016). The V302M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (K303R, A304V) have been reported in the Human Gene Mutation Database in association with GABRB2-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V302M as a pathogenic variant. -

Developmental and epileptic encephalopathy 92 Pathogenic:1

Mar 17, 2018

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;D;.;D;.;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;.;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.4	N;N;N;N;N;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.79
MutPred		0.71		Loss of methylation at K303 (P = 0.018);Loss of methylation at K303 (P = 0.018);Loss of methylation at K303 (P = 0.018);.;Loss of methylation at K303 (P = 0.018);.;.;
MVP		0.93
MPC		2.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.54
gMVP		0.93

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: rs1085307993; hg19: chr5-160758063;