chr17-4899465-T-TACGTGGCGCAGCCGCGGGG

Position:

• chr17-4899465-T-TACGTGGCGCAGCCGCGGGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 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. 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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.
• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1016_1032+2dupCCCCGCGGCTGCGCCACGT		splice_donor_variant, intron_variant		ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.980_996+2dupCCCCGCGGCTGCGCCACGT		splice_donor_variant, intron_variant			XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1016_1032+2dupCCCCGCGGCTGCGCCACGT		splice_donor_variant, intron_variant			NM_000080.4	ENSP00000497829.1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Breakthrough Genomics, Breakthrough Genomics

Oct 26, 2021

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

Likely pathogenic, no assertion criteria provided

clinical testing

Breakthrough Genomics, Breakthrough Genomics

Nov 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4802760;