rs28999110

Variant names:

• chr17-4901071-G-A
• rs28999110
• NM_000080.4:c.721C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-4901071-G-A
• chr17-4901071-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000080.4(CHRNE):​c.721C>T​(p.Leu241Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.14

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 17-4901071-G-A is Pathogenic according to our data. Variant chr17-4901071-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901071-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.721C>T	p.Leu241Phe	missense_variant	Exon 7 of 12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*538G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.721C>T	p.Leu241Phe	missense_variant	Exon 7 of 12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*538G>A		3_prime_UTR_variant	Exon 3 of 3	2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:3

Jun 21, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with clinical features of autosomal dominant congenital myasthenic syndrome (PMID: 12141316, 30542963). ClinVar contains an entry for this variant (Variation ID: 18352). This variant is also described as L221F in the literature. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects CHRNE protein function (PMID: 12141316, 22178625). 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 241 of the CHRNE protein (p.Leu241Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Jan 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 26, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome Pathogenic:1

Jun 25, 2024

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.721C>T (p.Leu241Phe) results in a non-conservative amino acid change in 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 250002 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.721C>T has been reported in the literature in multiple heterozygous individuals affected with slow-channel congenital myasthenic syndromes (Croxen_2002, Angelini_2019). Two publications report experimental evidence evaluating an impact on protein function. In one study in transient transfection into HEK293 cells, patch clamping showed 2.4-fold slow in time constant of decay of the synaptic current (Croxen_2002). In a mouse model carrying this missense variant, prolonged endplate currents was observed that is associated with moderate reduced muscle strength and tetanic fade, calcium and intracellular vesicle accumulation as well as junctional fold loss and organelle degeneration, and a remodeling of neuromuscular junctions (Chevessier_2012). The following publications have been ascertained in the context of this evaluation (PMID: 30542963, 22178625, 12141316). ClinVar contains an entry for this variant (Variation ID: 18352). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.012	D;.
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.91		Loss of catalytic residue at L241 (P = 0.008);Loss of catalytic residue at L241 (P = 0.008);
MVP		0.92
MPC		0.72
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.84
gMVP		0.72

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: rs28999110; hg19: chr17-4804366;