rs747853975

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000080.4(CHRNE):c.1211C>T(p.Thr404Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,604,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.193

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 Uncertain_significance. Variant got 0 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

BP4

Computational evidence support a benign effect (MetaRNN=0.22619289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4 link	c.1211C>T	p.Thr404Ile	missense_variant	Exon 10 of 12	ENST00000649488.2	NP_000071.1	Q04844
CHRNE	XM_017024115.2 link	c.1175C>T	p.Thr392Ile	missense_variant	Exon 11 of 13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2 link	c.1211C>T	p.Thr404Ile	missense_variant	Exon 10 of 12		NM_000080.4	ENSP00000497829.1		Q04844

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000478

GnomAD3 exomes

AF:

0.0000261

AC:

AN:

229716

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

126474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000592

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:

0.0000392

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000399

AC:

AN:

1452522

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

722474

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000450

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:

0.0000450

Gnomad4 OTH exome

AF:

0.0000832

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000478

Bravo

AF:

0.0000982

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 27, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 4A

Uncertain:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 404 of the CHRNE protein (p.Thr404Ile). This variant is present in population databases (rs747853975, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 585673). 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 not expected to disrupt CHRNE protein function with a negative predictive value of 95%. 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. -

Inborn genetic diseases

Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1211C>T (p.T404I) alteration is located in exon 10 (coding exon 10) of the CHRNE gene. This alteration results from a C to T substitution at nucleotide position 1211, causing the threonine (T) at amino acid position 404 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome

Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.30

.;T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.28

N;N;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.82

N;.;.

REVEL

Uncertain

0.29

Sift

Benign

0.13

T;.;.

Sift4G

Benign

0.13

T;.;.

Polyphen

0.17

B;B;.

Vest4

0.22

MutPred

0.59

Loss of disorder (P = 0.077);Loss of disorder (P = 0.077);.;

MVP

0.89

MPC

0.22

ClinPred

0.093

GERP RS

4.9

Varity_R

0.070

gMVP

0.25

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

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