rs606231468

chr5-161545228-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001371727.1(GABRB2):c.236T>C(p.Met79Thr) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M79I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GABRB2 NM_001371727.1 missense, splice_region
• Scores: Splicing: ADA: 0.4384
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.21

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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001371727.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRB2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 5-161545228-A-G is Pathogenic according to our data. Variant chr5-161545228-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 161444.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB2	NM_001371727.1	c.236T>C	p.Met79Thr	missense_variant, splice_region_variant	3/10	ENST00000393959.6
GABRB2	NM_021911.3	c.236T>C	p.Met79Thr	missense_variant, splice_region_variant	4/11
GABRB2	NM_000813.3	c.236T>C	p.Met79Thr	missense_variant, splice_region_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB2	ENST00000393959.6	c.236T>C	p.Met79Thr	missense_variant, splice_region_variant	3/10	1	NM_001371727.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epileptic encephalopathy, infantile or early childhood, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;.;D;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.7	H;H;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.
REVEL	Pathogenic	0.95
Sift	Benign	0.035	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.49	P;P;B;B;B;.
Vest4		0.97
MutPred		0.89		Loss of stability (P = 0.0094);Loss of stability (P = 0.0094);Loss of stability (P = 0.0094);.;Loss of stability (P = 0.0094);.;
MVP		0.94
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.57
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: rs606231468; hg19: chr5-160972234;