NM_000080.4:c.103T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP5

The NM_000080.4(CHRNE):c.103T>C(p.Tyr35His) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,613,994 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y35Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:2

Conservation

PhyloP100: 6.72

Publications

7 publications found

Variant links:

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]

CHRNE links:

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

C17orf107 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a topological_domain Extracellular (size 218) in uniprot entity ACHE_HUMAN there are 29 pathogenic changes around while only 6 benign (83%) in NM_000080.4

PP5

Variant 17-4902707-A-G is Pathogenic according to our data. Variant chr17-4902707-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282036.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4 link	c.103T>C	p.Tyr35His	missense_variant	Exon 2 of 12	ENST00000649488.2	NP_000071.1	Q04844
C17orf107	NM_001145536.2 link	c.*2174A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000381365.4	NP_001139008.1	Q6ZR85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNE	ENST00000649488.2 link	c.103T>C	p.Tyr35His	missense_variant	Exon 2 of 12		NM_000080.4	ENSP00000497829.1	Q04844
C17orf107	ENST00000381365.4 link	c.*2174A>G		3_prime_UTR_variant	Exon 3 of 3	2	NM_001145536.2	ENSP00000370770.3	Q6ZR85
CHRNE	ENST00000649830.1 link	c.-831T>C		5_prime_UTR_variant	Exon 2 of 11			ENSP00000496907.1	A0A3B3IRM1
CHRNE	ENST00000575637.1 link	n.-77T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000640

AC:

161

AN:

251424

AF XY:

0.000567

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00119

AC:

1740

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

796

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00147

AC:

1636

AN:

1112010

Other (OTH)

AF:

0.000894

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000651

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41474

American (AMR)

AF:

0.000524

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

67996

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00130

Hom.:

Bravo

AF:

0.000790

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000766

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Jul 29, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHRNE c.103T>C; p.Tyr35His variant (rs144169073, ClinVar Variation ID: 282036), also published as Y15H, is reported in the literature in multiple individuals affected with congenital myasthenic syndrome who carried a second variant in trans (Ealing 2002, Krenn 2023, McMacken 2018, Palace 2012, Webster 2014). This variant is found in the general population with an overall allele frequency of 0.06% (180/282,748 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.897). Based on available information, this variant is considered to be likely pathogenic. References: Ealing J et al. Mutations in congenital myasthenic syndromes reveal an epsilon subunit C-terminal cysteine, C470, crucial for maturation and surface expression of adult AChR. Hum Mol Genet. 2002 Nov 15;11(24):3087-96. PMID: 12417530. Krenn M et al. The clinical and molecular landscape of congenital myasthenic syndromes in Austria: a nationwide study. J Neurol. 2023 Feb;270(2):909-916. PMID: 36308527. McMacken G et al. Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients. J Neurol. 2018 Jan;265(1):194-203. PMID: 29189923. Palace J et al. Clinical features in a series of fast channel congenital myasthenia syndrome. Neuromuscul Disord. 2012 Feb;22(2):112-7. PMID: 21940170. Webster R et al. Fast-channel congenital myasthenic syndrome with a novel acetylcholine receptor mutation at the alpha-epsilon subunit interface. Neuromuscul Disord. 2014 Feb;24(2):143-7. PMID: 24295813. -

Dec 16, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Referred to as Y15H using alternate nomenclature; This variant is associated with the following publications: (PMID: 19544078, 21940170, 24295813, 29189923, 31980526, 17878953, 12417530, 36891870, 37091313) -

Oct 13, 2016

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 4A

Pathogenic:2

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 35 of the CHRNE protein (p.Tyr35His). This variant is present in population databases (rs144169073, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 12417530, 17878953, 21940170, 24295813). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Tyr15His. ClinVar contains an entry for this variant (Variation ID: 282036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CHRNE protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A

Pathogenic:1

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 4C

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tip-toe gait

Pathogenic:1

Nov 18, 2021

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

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. -

Congenital myasthenic syndrome 4B

Pathogenic:1

Nov 26, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Congenital myasthenic syndrome

Pathogenic:1

Dec 07, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHRNE c.103T>C (p.Tyr35His), also referred to as Y15H, results in a conservative amino acid change located in the neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251424 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CHRNE causing Congenital Myasthenic Syndrome (0.00064 vs 0.0025), allowing no conclusion about variant significance. c.103T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Congenital Myasthenic Syndrome (e.g. Ealing_2002, Denning_2007, Palace_2012, Webster_2014, McMacken_2018, Clair Hou_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31980526, 17878953, 12417530, 29189923, 21940170, 24295813). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters reported the variant as pathogenic/likely pathogenic and three as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A

Pathogenic:1

Feb 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1

Jan 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr35His variant in CHRNE has been reported in the compound heterozygous state in 6 indiv iduals with congenital myasthenic syndrome, and segregated with disease in two a ffected members of one family (reported as p.Tyr15His; Ealing 2002, Palace 2012, Webster 2014). It has also been identified in 0.1% (146/126616) of European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs144169073). In vitro functional studies provide some evidence tha t the p.Tyr35His variant may impact protein function (Ealing 2002). However, the se types of assays may not accurately represent biological function. Computation al prediction tools and conservation analysis also suggest that the variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, while there is some suspicion for a pathogenic role , the clinical significance of the p.Tyr35His variant is uncertain due to its fr equency in the general population. ACMG/AMP Criteria applied: PM3_Supporting; PS 4_Moderate; PP3; PS3_Supporting; BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.77

.;T

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

2.9

M;M

PhyloP100

6.7

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.2

D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.89

MVP

0.97

MPC

0.80

ClinPred

0.11

GERP RS

5.1

PromoterAI

0.032

Neutral

(source)

Varity_R

0.86

gMVP

0.93

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over