rs1555546096

Positions:

• chr17-4898838-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000080.4(CHRNE):​c.1380G>A​(p.Trp460Ter) variant causes a stop gained 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNE NM_000080.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.20

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0688 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-4898838-C-T is Pathogenic according to our data. Variant chr17-4898838-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 534250.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1380G>A	p.Trp460Ter	stop_gained	12/12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1344G>A	p.Trp448Ter	stop_gained	13/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1380G>A	p.Trp460Ter	stop_gained	12/12		NM_000080.4	ENSP00000497829	P1
CHRNE	ENST00000649830.1	c.*16G>A		3_prime_UTR_variant	11/11			ENSP00000496907
CHRNE	ENST00000572438.1	n.1066G>A		non_coding_transcript_exon_variant	7/7	5
CHRNE	ENST00000652550.1	n.1106G>A		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CHRNE protein in which other variant(s) (p.Tyr458*, p.Tyr478*) have been determined to be pathogenic (PMID: 12417530). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 534250). This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp460*) in the CHRNE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the CHRNE protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	D
Vest4		0.80
GERP RS		4.9

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: rs1555546096; hg19: chr17-4802133;