chr19-6361578-T-TGGCCCGGAATATTGGTAGGGGG
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006012.4(CLPP):c.12_33dup(p.Val12AsnfsTer70) variant causes a frameshift 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
CLPP
NM_006012.4 frameshift
NM_006012.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.68
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
?
Variant 19-6361578-T-TGGCCCGGAATATTGGTAGGGGG is Pathogenic according to our data. Variant chr19-6361578-T-TGGCCCGGAATATTGGTAGGGGG is described in ClinVar as [Pathogenic]. Clinvar id is 1356365.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLPP | NM_006012.4 | c.12_33dup | p.Val12AsnfsTer70 | frameshift_variant | 1/6 | ENST00000245816.11 | |
CLPP | XM_047439486.1 | c.12_33dup | p.Val12AsnfsTer102 | frameshift_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLPP | ENST00000245816.11 | c.12_33dup | p.Val12AsnfsTer70 | frameshift_variant | 1/6 | 1 | NM_006012.4 | P1 | |
ENST00000595644.1 | n.35+536_35+537insCCCCCTACCAATATTCCGGGCC | intron_variant, non_coding_transcript_variant | 4 | ||||||
CLPP | ENST00000596070.1 | n.22_43dup | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
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 | Sep 27, 2022 | ClinVar contains an entry for this variant (Variation ID: 1356365). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with CLPP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val12Asnfs*70) 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at