19-6361594-TA-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006012.4(CLPP):c.21del(p.Ala10ProfsTer117) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,412,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V7V) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000032 ( 0 hom. )
Consequence
CLPP
NM_006012.4 frameshift
NM_006012.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -3.06
Genes affected
CLPP (HGNC:2084): (caseinolytic mitochondrial matrix peptidase proteolytic subunit) The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 19-6361594-TA-T is Pathogenic according to our data. Variant chr19-6361594-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 2138190.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-6361594-TA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLPP | NM_006012.4 | c.21del | p.Ala10ProfsTer117 | frameshift_variant | 1/6 | ENST00000245816.11 | |
CLPP | XM_047439486.1 | c.21del | p.Ala10ProfsTer149 | frameshift_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLPP | ENST00000245816.11 | c.21del | p.Ala10ProfsTer117 | frameshift_variant | 1/6 | 1 | NM_006012.4 | P1 | |
ENST00000595644.1 | n.35+520del | intron_variant, non_coding_transcript_variant | 4 | ||||||
CLPP | ENST00000596070.1 | n.31del | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000317 AC: 4AN: 1260750Hom.: 0 Cov.: 32 AF XY: 0.00000164 AC XY: 1AN XY: 610460
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 30, 2022 | For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Perrault syndrome (PMID: 27899912). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala10Profs*117) in the CLPP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLPP are known to be pathogenic (PMID: 23851121, 27899912). - |
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at