rs759668768

Positions:

chr17-7445378-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000747.3(CHRNB1):c.167T>C(p.Val56Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000245 in 1,612,490 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

CHRNB1
NM_000747.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.13

Variant links:

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]

CHRNB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB1	NM_000747.3 linkuse as main transcript	c.167T>C	p.Val56Ala	missense_variant	2/11	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7 linkuse as main transcript	c.167T>C	p.Val56Ala	missense_variant	2/11	1	NM_000747.3	ENSP00000304290	P1	P11230-1
CHRNB1	ENST00000570557.5 linkuse as main transcript	c.41T>C	p.Val14Ala	missense_variant	1/8	5		ENSP00000460648
CHRNB1	ENST00000572857.5 linkuse as main transcript	c.167T>C	p.Val56Ala	missense_variant	2/6	4		ENSP00000461402
CHRNB1	ENST00000574054.1 linkuse as main transcript	n.187T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000160

AC:

AN:

243802

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

132896

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.000406

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000240

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000257

AC:

376

AN:

1460512

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000310

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000125

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 4C

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 22, 2024

Variant summary: CHRNB1 c.167T>C (p.Val56Ala) results in a non-conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 243802 control chromosomes in the gnomAD database, including 2 homozygotes. To our knowledge, no occurrence of c.167T>C in individuals affected with Congenital Myasthenic Syndrome 2C and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 523042). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital myasthenic syndrome 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 56 of the CHRNB1 protein (p.Val56Ala). This variant is present in population databases (rs759668768, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CHRNB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 523042). 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 not expected to disrupt CHRNB1 protein function with a negative predictive value of 80%. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.167T>C (p.V56A) alteration is located in exon 2 (coding exon 2) of the CHRNB1 gene. This alteration results from a T to C substitution at nucleotide position 167, causing the valine (V) at amino acid position 56 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.067

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.80

D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.6

D;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.84

P;.

Vest4

0.50

MVP

0.92

MPC

1.2

ClinPred

0.58

GERP RS

5.4

Varity_R

0.22

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over