17-4899465-T-TACGTGGCGCAGCCGCGGGG

Position:

• chr17-4899465-T-TACGTGGCGCAGCCGCGGGG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000080.4(CHRNE):​c.1032+2_1032+3insCCCCGCGGCTGCGCCACGT variant causes a splice region, 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 splice_region, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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 no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.1032+2_1032+3insCCCCGCGGCTGCGCCACGT		splice_region_variant, intron_variant		ENST00000649488.2
CHRNE	XM_017024115.2	c.996+2_996+3insCCCCGCGGCTGCGCCACGT		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.1032+2_1032+3insCCCCGCGGCTGCGCCACGT		splice_region_variant, intron_variant			NM_000080.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 4B Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Breakthrough Genomics, Breakthrough Genomics

-

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;