rs1553204015

chr1-154569551-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000748.3(CHRNB2):c.154G>A(p.Gly52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNB2 NM_000748.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.473

Genes affected

CHRNB2 (HGNC:1962): (cholinergic receptor nicotinic beta 2 subunit) Neuronal acetylcholine receptors are homo- or heteropentameric complexes composed of homologous alpha and beta subunits. They belong to a superfamily of ligand-gated ion channels which allow the flow of sodium and potassium across the plasma membrane in response to ligands such as acetylcholine and nicotine. This gene encodes one of several beta subunits. Mutations in this gene are associated with autosomal dominant nocturnal frontal lobe epilepsy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053556412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB2	NM_000748.3	c.154G>A	p.Gly52Ser	missense_variant	2/6	ENST00000368476.4
CHRNB2	XR_001736952.3	n.421G>A		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB2	ENST00000368476.4	c.154G>A	p.Gly52Ser	missense_variant	2/6	1	NM_000748.3	P4
CHRNB2	ENST00000637900.1	c.154G>A	p.Gly52Ser	missense_variant	2/6	5		A1
CHRNB2	ENST00000636695.1	n.24G>A		non_coding_transcript_exon_variant	1/3	5
CHRNB2	ENST00000636034.1	c.154G>A	p.Gly52Ser	missense_variant, NMD_transcript_variant	2/9	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CHRNB2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 52 of the CHRNB2 protein (p.Gly52Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Benign	0.87
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.5	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.76	N;.
REVEL	Uncertain	0.40
Sift	Benign	0.98	T;.
Sift4G	Benign	0.84	T;.
Polyphen		0.044	B;.
Vest4		0.18
MutPred		0.33		Gain of disorder (P = 0.0933);Gain of disorder (P = 0.0933);
MVP		0.61
MPC		1.1
ClinPred		0.50	D
GERP RS		4.8
Varity_R		0.46
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553204015; hg19: chr1-154542027;