17-4900809-C-T

Variant names:

• chr17-4900809-C-T
• rs140023380
• NM_000080.4:c.901G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000080.4(CHRNE):​c.901G>A​(p.Val301Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,613,810 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V301L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 2.17
• Publications: 3 publications found

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000080.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.08342728).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.901G>A	p.Val301Met	missense	Exon 8 of 12	NP_000071.1
	C17orf107	NM_001145536.2	MANE Select	c.*276C>T		3_prime_UTR	Exon 3 of 3	NP_001139008.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.901G>A	p.Val301Met	missense	Exon 8 of 12	ENSP00000497829.1
	C17orf107	ENST00000381365.4	TSL:2 MANE Select	c.*276C>T		3_prime_UTR	Exon 3 of 3	ENSP00000370770.3
	CHRNE	ENST00000649830.1		c.-33G>A		5_prime_UTR_premature_start_codon_gain	Exon 8 of 11	ENSP00000496907.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000705 AC: 175 AN: 248052 AF XY: 0.000728

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000893

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000596 AC: 871 AN: 1461574 Hom.: 1 Cov.: 33 AF XY: 0.000602 AC XY: 438 AN XY: 727090

African (AFR) AF: 0.000239 AC: 8 AN: 33472

American (AMR) AF: 0.000291 AC: 13 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86246

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53372

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000638 AC: 709 AN: 1111830

Other (OTH) AF: 0.000398 AC: 24 AN: 60376

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74378

African (AFR) AF: 0.000314 AC: 13 AN: 41464

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000558 AC: 38 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000733 Hom.: 0

Bravo AF: 0.000601

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.00120

EpiControl AF: 0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 05, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Tip-toe gait Pathogenic:1

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.901G> A p. (Val301Met), which is listed in the dbSNP database [dbSNP: rs140023380 frequency A = 0.0711% (ExAC)], was found heterozygous in the CHRNE gene. In the ClinVar database, it is rated inconsistently with regard to its clinical effects (2x probably benign, 1x VUS). In the locus-specific database LOVD, it is also assessed as a variant of unclear significance. The variant causes the exchange of the amino acid valine at position 301 by methionine in the highly conserved second extracellular topological domain of the epsilon subunit of the acetylcholine receptor, which can influence the protein structure due to the steric differences between the two amino acids. The variant has not yet been described in the literature, but variants in the neighboring codons have been associated with the congenital myasthenia syndrome as pathological. A pathological influence is supported by the results of in-silico calculations; PolyPhen-2 "possibly damaging", MutationTaster "disease causing", MutationAssessor "medium impact". The fact that the patient has a "de novo" mutation may also indicate that it is a pathogenic mutation. Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

not provided Uncertain:1

Apr 02, 2025

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 02, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Congenital myasthenic syndrome 4A Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHRNE-related disorder Benign:1

May 21, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.083	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.95	P
Vest4		0.43
MVP		0.90
MPC		0.34
ClinPred		0.14	T
GERP RS		5.0
Varity_R		0.71
gMVP		0.71
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs140023380; hg19: chr17-4804104; COSMIC: COSV99036234; COSMIC: COSV99036234;