chr17-4899465-T-TACGTGGCGCAGCCGCGGGG

Variant names:

• chr17-4899465-T-TACGTGGCGCAGCCGCGGGG
• ENST00000521575.1:c.-295_-277dupGTGGCGCAGCCGCGGGGAC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000080.4(CHRNE):​c.1016_1032+2dupCCCCGCGGCTGCGCCACGT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.14
• Publications: 1 publications found

Genes affected

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

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]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.6, offset of 19, new splice context is: cacGTaagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 17-4899465-T-TACGTGGCGCAGCCGCGGGG is Pathogenic according to our data. Variant chr17-4899465-T-TACGTGGCGCAGCCGCGGGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2692228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1016_1032+2dupCCCCGCGGCTGCGCCACGT		splice_donor_variant, intron_variant	Intron 9 of 11	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.-298_-297insACGTGGCGCAGCCGCGGGG		upstream_gene_variant		ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1016_1032+2dupCCCCGCGGCTGCGCCACGT		splice_donor_variant, intron_variant	Intron 9 of 11		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.-298_-297insACGTGGCGCAGCCGCGGGG		upstream_gene_variant		2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 4B Pathogenic:1

Oct 26, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant seems to be a novel variant, as it has not been previously reported in population or public databases or in the literature. However, splice variants, lying downstream of the variant, have been reported as pathogenic/likely pathogenic in the ClinVar database in the context of slow-channel congenital myasthenic syndrome 4a. Loss-of-function variants in the CHRNE are known to be pathogenic [PMID: 22678886] -

Congenital myasthenic syndrome Pathogenic:1

Nov 26, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

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

Other links and lift over

hg19: chr17-4802760;