rs1168592296

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000080.4(CHRNE):c.1052C>T(p.Pro351Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000847 in 1,534,296 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 5.25

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 made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 127) in uniprot entity ACHE_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000080.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 17-4899365-G-A is Pathogenic according to our data. Variant chr17-4899365-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465851.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr17-4899365-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4 link	c.1052C>T	p.Pro351Leu	missense_variant	Exon 10 of 12	ENST00000649488.2	NP_000071.1	Q04844
C17orf107	NM_001145536.2 link	c.-398G>A		upstream_gene_variant		ENST00000381365.4	NP_001139008.1	Q6ZR85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2 link	c.1052C>T	p.Pro351Leu	missense_variant	Exon 10 of 12		NM_000080.4	ENSP00000497829.1		Q04844
C17orf107	ENST00000381365.4 link	c.-398G>A		upstream_gene_variant		2	NM_001145536.2	ENSP00000370770.3		Q6ZR85

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000868

AC:

AN:

1382156

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

682604

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000111

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 4C

Pathogenic:1

Oct 05, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 11408331). In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.69 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with CHRNE related disorder (ClinVar ID: VCV000465851 /PMID: 11408331). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 11408331). A different missense change at the same codon (p.Pro351Arg) has been reported to be associated with CHRNE related disorder (ClinVar ID: VCV002577839). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

CHRNE-related disorder

Pathogenic:1

Mar 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHRNE c.1052C>T variant is predicted to result in the amino acid substitution p.Pro351Leu. This variant, described as p.Pro331Leu based on legacy nomenclature, was reported in the homozygous state in two affected siblings with congenital myasthenic syndrome (Croxen et al. 2001. PubMed ID: 11408331). In expression studies, the p.Pro351Leu substitution was reported to severely reduce surface expression of acetylcholine receptor (Croxen et al. 2001. PubMed ID: 11408331). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), although it should be noted that coverage of this region is absent in the gnomAD exome dataset and therefore allele frequency data may be not be accurate. This variant is interpreted as likely pathogenic. -

Congenital myasthenic syndrome

Pathogenic:1

Jul 20, 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.1052C>T (p.Pro351Leu) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Neurotransmitter-gated ion-channel transmembrane domain (IPR006029) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 131104 control chromosomes (gnomAD). c.1052C>T has been reported in the literature in related homozygous individuals affected with Congenital Myasthenic Syndrome and AChR deficiency, showing evidence of cosegregation with disease in this family (Croxen_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that HEK293 cells expressing the epsilon-subunit with the variant lack the ability to bind alpha-Bungarotoxin, and that the protein fails to incorporate into the surface AChR complex (Croxen_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11408331). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital myasthenic syndrome 4A

Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 351 of the CHRNE protein (p.Pro351Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This missense change has been observed in individual(s) with congenital myasthenic syndrome (CMS) (PMID: 11408331). It has also been observed to segregate with disease in related individuals. This variant is also known as c.992C>T; p.P331L. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CHRNE function (PMID: 11408331). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

.;T;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.2

H;H;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.6

D;.;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0020

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.78

MutPred

0.88

Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;

MVP

0.95

MPC

0.70

ClinPred

1.0

GERP RS

4.9

Varity_R

0.86

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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