rs121909514

chr17-4901932-C-A

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.500G>T(p.Arg167Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.71

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 2 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-4901932-C-A is Pathogenic according to our data. Variant chr17-4901932-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901932-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.500G>T	p.Arg167Leu	missense_variant, splice_region_variant	5/12	ENST00000649488.2
C17orf107	NM_001145536.2	c.*1399C>A		3_prime_UTR_variant	3/3	ENST00000381365.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.500G>T	p.Arg167Leu	missense_variant, splice_region_variant	5/12		NM_000080.4	P1
C17orf107	ENST00000381365.4	c.*1399C>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	A2
CHRNE	ENST00000649830.1	c.-434G>T		splice_region_variant, 5_prime_UTR_variant	5/11
CHRNE	ENST00000575637.1	n.274+47G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152030 Hom.: 0 Cov.: 32

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: 0.00000274 AC: 4 AN: 1461256 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726922

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74250

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: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 167 of the CHRNE protein (p.Arg167Leu). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9158150). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18345). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CHRNE function (PMID: 9158150). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 11, 2023	- -

Congenital myasthenic syndrome 4C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2022

Published functional studies demonstrate significantly reduced surface expression of the acetylcholine receptors (Ohno et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 9158150) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.029	D;.
Sift4G	Uncertain	0.057	T;.
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.90		Loss of catalytic residue at R167 (P = 0.0138);Loss of catalytic residue at R167 (P = 0.0138);
MVP		0.91
MPC		0.76
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909514; hg19: chr17-4805227; COSMIC: COSV53420593; COSMIC: COSV53420593;