rs137852810

Positions:

• chr17-7454341-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000747.3(CHRNB1):​c.865G>A​(p.Val289Met) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V289A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.05

Genes affected

CHRNB1 (HGNC:1961): (cholinergic receptor nicotinic beta 1 subunit) The muscle acetylcholine receptor is composed of five subunits: two alpha subunits and one beta, one gamma, and one delta subunit. This gene encodes the beta subunit of the acetylcholine receptor. The acetylcholine receptor changes conformation upon acetylcholine binding leading to the opening of an ion-conducting channel across the plasma membrane. Mutations in this gene are associated with slow-channel congenital myasthenic syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a transmembrane_region Helical (size 18) in uniprot entity ACHB_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000747.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7454342-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 860460.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 17-7454341-G-A is Pathogenic according to our data. Variant chr17-7454341-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7454341-G-A is described in UniProt as null. Variant chr17-7454341-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB1	NM_000747.3	c.865G>A	p.Val289Met	missense_variant	8/11	ENST00000306071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB1	ENST00000306071.7	c.865G>A	p.Val289Met	missense_variant	8/11	1	NM_000747.3	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 2A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 09, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNB1 function (PMID: 8872460). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 18372). This missense change has been observed in individuals with autosomal dominant slow-channel congenital myasthenic syndrome (PMID: 8872460, 20562457, 27391121). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 289 of the CHRNB1 protein (p.Val289Met). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	Published functional studies demonstrate a damaging effect (pathologic channel opening) (PMID: 8872460); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27391121, 20562457, 8872460, 32895905) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.91		Loss of catalytic residue at V289 (P = 0.0963);.;
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.68
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852810; hg19: chr17-7357660;