rs121909516

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000080.4(CHRNE):c.488C>T(p.Ser163Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,612,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 10.0

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:

C17orf107 (HGNC:):

C17orf107 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a topological_domain Extracellular (size 218) in uniprot entity ACHE_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000080.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 17-4901944-G-A is Pathogenic according to our data. Variant chr17-4901944-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901944-G-A is described in Lovd as [Pathogenic]. Variant chr17-4901944-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4 linkuse as main transcript	c.488C>T	p.Ser163Leu	missense_variant	5/12	ENST00000649488.2	NP_000071.1	Q04844
C17orf107	NM_001145536.2 linkuse as main transcript	c.*1411G>A		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1	Q6ZR85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2 linkuse as main transcript	c.488C>T	p.Ser163Leu	missense_variant	5/12		NM_000080.4	ENSP00000497829.1		Q04844
C17orf107	ENST00000381365.4 linkuse as main transcript	c.*1411G>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770.3		Q6ZR85

Frequencies

GnomAD3 genomes

AF:

0.000291

AC:

AN:

151446

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000954

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000530

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000272

AC:

AN:

250058

Hom.:

AF XY:

0.000318

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000498

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000506

AC:

739

AN:

1460812

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

347

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000403

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:

0.000625

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000290

AC:

AN:

151560

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

74070

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.0000954

Gnomad4 NFE

AF:

0.000530

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000457

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000889

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2024	Published functional studies demonstrate a damaging effect with failure of protein product to assemble with the alpha subunit of the acetylcholine receptor (PMID: 8755487); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.S143L; This variant is associated with the following publications: (PMID: 32403337, 33199334, 37091313, 8755487) -
Uncertain significance, flagged submission	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CHRNE p.S163L variant was identified in the literature in two compound heterozygous siblings with congenital myasthenic syndrome (Ohno_1996_PMID:8755487).Â¬â€ The variant was identified in dbSNP (ID: rs121909516) and ClinVar (classified as uncertain significance by Invitae and Illumina; as likely pathogenic by GeneDx and Baylor Genetics; and as pathogenic by OMIM).Â¬â€ The variant was identified in control databases in 74 of 281378 chromosomes at a frequency of 0.0002630, and was observed at the highest frequency in the European (non-Finnish) population in 60 of 127756 chromosomes (freq: 0.0004696) (Genome Aggregation Database March 6, 2019, v2.1.1).Â¬â€ The p.S163 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional analysis of the p.S163L variant demonstrates reduced protein expression compared to wildtype and impaired acetylcholine receptor subunit assembly (Ohno_1996_PMID:8755487).Â¬â€ The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome, Splice AI genome) do not predict a difference in splicing.Â¬â€ In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 10, 2021	- -

Congenital myasthenic syndrome 4A

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 163 of the CHRNE protein (p.Ser163Leu). This variant is present in population databases (rs121909516, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 8755487). 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 S143L. ClinVar contains an entry for this variant (Variation ID: 18360). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHRNE protein function. Experimental studies have shown that this missense change affects CHRNE function (PMID: 8755487). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Tip-toe gait

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

Nov 12, 2020

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CHRNE-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

The CHRNE c.488C>T variant is predicted to result in the amino acid substitution p.Ser163Leu. This variant has previously been reported in the compound heterozygous state in two siblings with autosomal recessive fast-channel congenital myasthenic syndrome 4B, and functional studies support its pathogenicity (Ohno et al. 1996. PubMed: 8755487, reported as S143L). It is documented in an additional affected individual from a neuromuscular disorders patient cohort; however, zygosity of this variant and patient phenotype were not defined (Gonzalez-Quereda L et al 2020. PubMed ID: 32403337). This variant is reported in 0.047% of alleles in individuals of European (non-Finnish) descent in gnomAD, and the majority of ClinVar entries indicate this variant is likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/18360/evidence/). This variant is interpreted as likely pathogenic. -

Congenital myasthenic syndrome 4B

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

D;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.82

MVP

0.93

MPC

0.65

ClinPred

0.68

GERP RS

4.6

Varity_R

0.78

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over