17-7445150-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000747.3(CHRNB1):​c.23T>G​(p.Met8Arg) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CHRNB1
NM_000747.3 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.577
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]
FGF11 (HGNC:3667): (fibroblast growth factor 11) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. The function of this gene has not yet been determined. The expression pattern of the mouse homolog implies a role in nervous system development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30854464).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNB1NM_000747.3 linkc.23T>G p.Met8Arg missense_variant Exon 1 of 11 ENST00000306071.7 NP_000738.2 P11230-1
FGF11NM_004112.4 linkc.*2004T>G downstream_gene_variant ENST00000293829.9 NP_004103.1 Q92914A0A7U3JVZ5
FGF11NM_001303460.2 linkc.*2004T>G downstream_gene_variant NP_001290389.1 Q92914B7Z1C3
FGF11NR_130156.2 linkn.*213T>G downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNB1ENST00000306071.7 linkc.23T>G p.Met8Arg missense_variant Exon 1 of 11 1 NM_000747.3 ENSP00000304290.2 P11230-1
FGF11ENST00000293829.9 linkc.*2004T>G downstream_gene_variant 1 NM_004112.4 ENSP00000293829.4 Q92914

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 2A Uncertain:1
Aug 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with CHRNB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 8 of the CHRNB1 protein (p.Met8Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.051
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
20
DANN
Benign
0.94
DEOGEN2
Benign
0.25
T;.
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.41
N
M_CAP
Benign
0.078
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.0
N;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.3
N;.
REVEL
Uncertain
0.41
Sift
Benign
0.066
T;.
Sift4G
Uncertain
0.041
D;D
Polyphen
0.0050
B;.
Vest4
0.61
MutPred
0.68
Gain of methylation at M8 (P = 0.0084);Gain of methylation at M8 (P = 0.0084);
MVP
0.82
MPC
0.62
ClinPred
0.26
T
GERP RS
4.5
Varity_R
0.54
gMVP
0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7348469; API