rs121909510

chr17-4900860-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000080.4(CHRNE):c.850A>C(p.Thr284Pro) variant causes a missense change involving the alteration of a non-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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T284I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.81

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000080.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-4900860-T-G is Pathogenic according to our data. Variant chr17-4900860-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4900860-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.850A>C	p.Thr284Pro	missense_variant	8/12	ENST00000649488.2
C17orf107	NM_001145536.2	c.*327T>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.850A>C	p.Thr284Pro	missense_variant	8/12		NM_000080.4	P1
C17orf107	ENST00000381365.4	c.*327T>G		3_prime_UTR_variant	3/3	2	NM_001145536.2	A2
CHRNE	ENST00000649830.1	c.-84A>C		5_prime_UTR_variant	8/11
CHRNE	ENST00000572438.1	n.536A>C		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 07, 2018	This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 284 of the CHRNE protein (p.Thr284Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant has been reported to be de novo in individuals affected with congenital myasthenic syndrome (PMID: 7531341, Invitae). This variant is also known as c.790A>C, p.Thr264Pro in the literature (PMID: 7531341). ClinVar contains an entry for this variant (Variation ID: 18343). Experimental studies have shown that this missense change results in altered channel properties of the CHRNE protein (PMID: 7531341). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 31, 1995	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.96		Loss of stability (P = 0.2883);Loss of stability (P = 0.2883);
MVP		0.97
MPC		0.80
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.95

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: rs121909510; hg19: chr17-4804155;