chr17-4901171-GATGGCCC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.32
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 18357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4901171-GATGGCCC-G is described in Lovd as [Pathogenic]. Variant chr17-4901171-GATGGCCC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNENM_000080.4 linkc.614_620delGGGCCAT p.Trp205SerfsTer7 frameshift_variant Exon 7 of 12 ENST00000649488.2 NP_000071.1 Q04844
C17orf107NM_001145536.2 linkc.*640_*646delTGGCCCA 3_prime_UTR_variant Exon 3 of 3 ENST00000381365.4 NP_001139008.1 Q6ZR85

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNEENST00000649488.2 linkc.614_620delGGGCCAT p.Trp205SerfsTer7 frameshift_variant Exon 7 of 12 NM_000080.4 ENSP00000497829.1 Q04844
C17orf107ENST00000381365.4 linkc.*640_*646delTGGCCCA 3_prime_UTR_variant Exon 3 of 3 2 NM_001145536.2 ENSP00000370770.3 Q6ZR85

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152182
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.0000372
AC:
9
AN:
241986
Hom.:
0
AF XY:
0.0000227
AC XY:
3
AN XY:
132184
show subpopulations
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 SAS 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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000301
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152182
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000680

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Sep 11, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 02, 2023
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) -

Congenital myasthenic syndrome Pathogenic:3
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 01, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
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. -

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 v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753828284; hg19: chr17-4804466; API