rs121909510

Variant names:

• chr17-4900860-T-G
• rs121909510
• NM_000080.4:c.850A>C

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 4 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 18343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.850A>C	p.Thr284Pro	missense_variant	Exon 8 of 12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*327T>G		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.850A>C	p.Thr284Pro	missense_variant	Exon 8 of 12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*327T>G		3_prime_UTR_variant	Exon 3 of 3	2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

May 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change results in altered channel properties of the CHRNE protein (PMID: 7531341). 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). 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. -

Jan 31, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H
PhyloP100		2.8
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909510; hg19: chr17-4804155;