rs753828284

Variant names:

• chr17-4901171-GATGGCCC-G
• rs753828284
• NM_000080.4:c.614_620delGGGCCAT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000080.4(CHRNE):​c.614_620delGGGCCAT​(p.Trp205SerfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,606,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CHRNE NM_000080.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.32
• Publications: 2 publications found

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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-4901171-GATGGCCC-G is Pathogenic according to our data. Variant chr17-4901171-GATGGCCC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 18357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.614_620delGGGCCAT	p.Trp205SerfsTer7	frameshift	Exon 7 of 12	NP_000071.1
	C17orf107	NM_001145536.2	MANE Select	c.*640_*646delTGGCCCA		3_prime_UTR	Exon 3 of 3	NP_001139008.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.614_620delGGGCCAT	p.Trp205SerfsTer7	frameshift	Exon 7 of 12	ENSP00000497829.1
	C17orf107	ENST00000381365.4	TSL:2 MANE Select	c.*640_*646delTGGCCCA		3_prime_UTR	Exon 3 of 3	ENSP00000370770.3
	CHRNE	ENST00000572438.1	TSL:5	n.300_306delGGGCCAT		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000372 AC: 9 AN: 241986 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000719

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000233 AC: 339 AN: 1454758 Hom.: 0 AF XY: 0.000203 AC XY: 147 AN XY: 723842

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000301 AC: 335 AN: 1111384

Other (OTH) AF: 0.0000663 AC: 4 AN: 60304

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Mar 19, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (null allele) (Ohno et al., 1997); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9158150, 14532324, 31589614)

Sep 11, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHRNE c.614_620delGGGCCAT (p.Trp205SerfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.7e-05 in 241986 control chromosomes. c.614_620delGGGCCAT has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome (example, Ohno_2003). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Dec 01, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome 4A Pathogenic:2

Feb 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp205Serfs*7) in the CHRNE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNE are known to be pathogenic (PMID: 22678886). This variant is present in population databases (rs753828284, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 9158150; internal data). This variant is also known as 553del7. ClinVar contains an entry for this variant (Variation ID: 18357). For these reasons, this variant has been classified as Pathogenic.

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Pathogenic:1

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome 4C Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Congenital myasthenic syndrome 4B Pathogenic:1

Dec 31, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant in exon 7 of 12 introduces a premature stop codon and is predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous or homozygous change in multiple individuals with congenital myasthenic syndrome (PMID: 9158150, 14532324). Segregation analyses of unaffected family members have indicated this variant acts in a recessive fashion (PMID: 14532324). Functional studies performed in HEK cells have shown the c.614_620del (p.Trp205SerfsTer7) variant is a null mutation (PMID: 9158150). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (11/273326) and thus is presumed to be rare. Based on the available evidence, this variant is classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs753828284; hg19: chr17-4804466;