17-4902707-A-G

Position:

• chr17-4902707-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

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 Likely pathogenic (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:2
• Conservation: PhyloP100: 6.72

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Extracellular (size 218) in uniprot entity ACHE_HUMAN there are 49 pathogenic changes around while only 5 benign (91%) 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 [Likely_pathogenic]. Clinvar id is 282036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4902707-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.103T>C	p.Tyr35His	missense_variant	2/12	ENST00000649488.2
C17orf107	NM_001145536.2	c.*2174A>G		3_prime_UTR_variant	3/3	ENST00000381365.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.103T>C	p.Tyr35His	missense_variant	2/12		NM_000080.4	P1
C17orf107	ENST00000381365.4	c.*2174A>G		3_prime_UTR_variant	3/3	2	NM_001145536.2	A2
CHRNE	ENST00000649830.1	c.-831T>C		5_prime_UTR_variant	2/11

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 151998 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000640 AC: 161 AN: 251424 Hom.: 0 AF XY: 0.000567 AC XY: 77 AN XY: 135894

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 SAS exome AF: 0.0000653

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.: 1 Cov.: 35 AF XY: 0.00109 AC XY: 796 AN XY: 727242

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000651 AC: 99 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74352

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000790

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00172

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 16, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 13, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2023	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) -

Congenital myasthenic syndrome 4A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 18, 2021

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 4C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Congenital myasthenic syndrome 4B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 26, 2019

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

Congenital myasthenic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

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. -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 10, 2018

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	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
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	T
GERP RS		5.1
Varity_R		0.86
gMVP		0.93

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: rs144169073; hg19: chr17-4806002;