ENST00000521575:c.-295_-277dupGTGGCGCAGCCGCGGGGAC

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000521575(C17orf107):​c.-295_-277dupGTGGCGCAGCCGCGGGGAC variant causes a 5 prime UTR 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: C17orf107 ENST00000521575 5_prime_UTR
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 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

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;