17-4900809-C-T

Position:

• chr17-4900809-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. 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).

• 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

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)

CHRNE (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08342728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.901G>A	p.Val301Met	missense_variant	8/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*276C>T		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.901G>A	p.Val301Met	missense_variant	8/12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*276C>T		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770.3

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

GnomAD3 exomes AF: 0.000705 AC: 175 AN: 248052 Hom.: 1 AF XY: 0.000728 AC XY: 98 AN XY: 134644

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 SAS exome AF: 0.000229

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

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000638

Gnomad4 OTH exome AF: 0.000398

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

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000558

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000840 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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 05, 2020	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

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

-

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

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 15, 2023

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

CHRNE-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2020

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 v4.3

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;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;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.1	M;M
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;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

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