5-161294221-G-T

Variant names:

• chr5-161294221-G-T
• rs2113333399
• NM_001371727.1:c.1399C>A

Variant summary

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

The NM_001371727.1(GABRB2):​c.1399C>A​(p.Leu467Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L467L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.87
• 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.1399C>A	p.Leu467Met	missense_variant	Exon 10 of 10	ENST00000393959.6	NP_001358656.1
GABRB2	NM_021911.3	c.1399C>A	p.Leu467Met	missense_variant	Exon 11 of 11		NP_068711.1
GABRB2	NM_000813.3	c.1285C>A	p.Leu429Met	missense_variant	Exon 10 of 10		NP_000804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB2	ENST00000393959.6	c.1399C>A	p.Leu467Met	missense_variant	Exon 10 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	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.;T;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.057	T;T;T;T;T;T
Sift4G	Benign	0.070	T;T;T;T;T;T
Polyphen		1.0	D;D;P;P;P;D
Vest4		0.44
MutPred		0.56		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;.;.;
MVP		0.79
MPC		0.75
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.22
gMVP		0.57
Mutation Taster		=18/82	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: rs2113333399; hg19: chr5-160721228;