NM_001371727.1:c.1531G>A

Variant names:

• chr5-161294089-C-T
• rs77133486
• NM_001371727.1:c.1531G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001371727.1(GABRB2):​c.1531G>A​(p.Val511Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 0 publications found

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]

GABRB2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 92

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371727.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB2	NM_001371727.1	MANE Select	c.1531G>A	p.Val511Met	missense	Exon 10 of 10	NP_001358656.1	P47870-2
	GABRB2	NM_021911.3		c.1531G>A	p.Val511Met	missense	Exon 11 of 11	NP_068711.1	P47870-2
	GABRB2	NM_000813.3		c.1417G>A	p.Val473Met	missense	Exon 10 of 10	NP_000804.1	P47870-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB2	ENST00000393959.6	TSL:1 MANE Select	c.1531G>A	p.Val511Met	missense	Exon 10 of 10	ENSP00000377531.1	P47870-2
	GABRB2	ENST00000353437.10	TSL:1	c.1417G>A	p.Val473Met	missense	Exon 10 of 10	ENSP00000274546.6	P47870-1
	GABRB2	ENST00000520240.5	TSL:1	c.1417G>A	p.Val473Met	missense	Exon 10 of 10	ENSP00000429320.1	P47870-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.45
Sift	Benign	0.10	T
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.56
MutPred		0.47		Loss of sheet (P = 0.0817)
MVP		0.74
MPC		0.39
ClinPred		0.77	D
GERP RS		4.9
Varity_R		0.18
gMVP		0.58
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs77133486; hg19: chr5-160721096;