17-7445158-G-A

Variant names:

• chr17-7445158-G-A
• rs1908543374
• NM_000747.3:c.31G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000747.3(CHRNB1):​c.31G>A​(p.Gly11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300

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]

ENSG00000272884 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.31G>A	p.Gly11Arg	missense_variant	Exon 1 of 11	ENST00000306071.7	NP_000738.2
FGF11	NM_004112.4	c.*2012G>A		downstream_gene_variant		ENST00000293829.9	NP_004103.1
FGF11	NM_001303460.2	c.*2012G>A		downstream_gene_variant			NP_001290389.1
FGF11	NR_130156.2	n.*221G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.31G>A	p.Gly11Arg	missense_variant	Exon 1 of 11	1	NM_000747.3	ENSP00000304290.2
FGF11	ENST00000293829.9	c.*2012G>A		downstream_gene_variant		1	NM_004112.4	ENSP00000293829.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 2A Uncertain:1

Jan 27, 2020

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. This sequence change replaces glycine with arginine at codon 11 of the CHRNB1 protein (p.Gly11Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHRNB1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.026
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.64	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.11	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.58	P;.
Vest4		0.71
MutPred		0.42		Gain of methylation at G11 (P = 0.0263);Gain of methylation at G11 (P = 0.0263);
MVP		0.85
MPC		0.48
ClinPred		0.74	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.18
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

Other links and lift over

dbSNP: rs1908543374; hg19: chr17-7348477;