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
Consequence
NM_000080.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.614_620delGGGCCAT | p.Trp205SerfsTer7 | frameshift_variant | Exon 7 of 12 | ENST00000649488.2 | NP_000071.1 | |
C17orf107 | NM_001145536.2 | c.*640_*646delTGGCCCA | 3_prime_UTR_variant | Exon 3 of 3 | ENST00000381365.4 | NP_001139008.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.614_620delGGGCCAT | p.Trp205SerfsTer7 | frameshift_variant | Exon 7 of 12 | NM_000080.4 | ENSP00000497829.1 | |||
C17orf107 | ENST00000381365.4 | c.*640_*646delTGGCCCA | 3_prime_UTR_variant | Exon 3 of 3 | 2 | NM_001145536.2 | ENSP00000370770.3 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000372 AC: 9AN: 241986Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132184
GnomAD4 exome AF: 0.000233 AC: 339AN: 1454758Hom.: 0 AF XY: 0.000203 AC XY: 147AN XY: 723842
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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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
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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
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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
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Congenital myasthenic syndrome 4C Pathogenic:1
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Congenital myasthenic syndrome 4B Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at