rs193920932

Variant names:

• chr5-161336734-G-A
• rs193920932
• NM_001371727.1:c.577C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001371727.1(GABRB2):​c.577C>T​(p.Arg193Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,610,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R193H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.57
• Publications: 6 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.577C>T	p.Arg193Cys	missense	Exon 6 of 10	NP_001358656.1	P47870-2
	GABRB2	NM_021911.3		c.577C>T	p.Arg193Cys	missense	Exon 7 of 11	NP_068711.1	P47870-2
	GABRB2	NM_000813.3		c.577C>T	p.Arg193Cys	missense	Exon 7 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.577C>T	p.Arg193Cys	missense	Exon 6 of 10	ENSP00000377531.1	P47870-2
	GABRB2	ENST00000353437.10	TSL:1	c.577C>T	p.Arg193Cys	missense	Exon 7 of 10	ENSP00000274546.6	P47870-1
	GABRB2	ENST00000520240.5	TSL:1	c.577C>T	p.Arg193Cys	missense	Exon 7 of 10	ENSP00000429320.1	P47870-1

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149270 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461052 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 726832

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111640

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149270 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72460

African (AFR) AF: 0.00 AC: 0 AN: 40370

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67684

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability (1)
-	1	-	Prostate cancer (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.053	T
Polyphen		0.88	P
Vest4		0.69
MutPred		0.55		Gain of sheet (P = 0.0827)
MVP		0.88
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.94
Mutation Taster		=25/75	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: rs193920932; hg19: chr5-160763741; COSMIC: COSV50906596;