chr5-161330900-G-C

Variant names:

• chr5-161330900-G-C
• rs41298406
• NM_001371727.1:c.1060C>G

Variant summary

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

The NM_001371727.1(GABRB2):​c.1060C>G​(p.Arg354Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R354S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80
• 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):

• developmental and epileptic encephalopathy 92

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB2	NM_001371727.1	c.1060C>G	p.Arg354Gly	missense_variant	Exon 8 of 10	ENST00000393959.6	NP_001358656.1
GABRB2	NM_021911.3	c.1060C>G	p.Arg354Gly	missense_variant	Exon 9 of 11		NP_068711.1
GABRB2	NM_000813.3	c.1060C>G	p.Arg354Gly	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.1060C>G	p.Arg354Gly	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.;T;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	.;T;.;T;T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;L;L;.;L;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.091	T;T;D;T;D;D;.
Sift4G	Uncertain	0.043	D;D;T;T;T;T;T
Polyphen		0.75	P;P;B;B;B;P;.
Vest4		0.71
MVP		0.99
MPC		0.42
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.87
Mutation Taster		=16/84	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: rs41298406; hg19: chr5-160757907;