rs587777042
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001916.5(CYC1):c.643C>T(p.Leu215Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CYC1
NM_001916.5 missense
NM_001916.5 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 5.73
Genes affected
CYC1 (HGNC:2579): (cytochrome c1) This gene encodes a subunit of the cytochrome bc1 complex, which plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein to cytochrome c. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear type 6. [provided by RefSeq, Dec 2013]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 8-144096615-C-T is Pathogenic according to our data. Variant chr8-144096615-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66020.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYC1 | NM_001916.5 | c.643C>T | p.Leu215Phe | missense_variant | 5/7 | ENST00000318911.5 | NP_001907.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYC1 | ENST00000318911.5 | c.643C>T | p.Leu215Phe | missense_variant | 5/7 | 1 | NM_001916.5 | ENSP00000317159.4 | ||
CYC1 | ENST00000533444.1 | n.1308C>T | non_coding_transcript_exon_variant | 4/6 | 1 | |||||
CYC1 | ENST00000525122.1 | n.271C>T | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251278Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135812
GnomAD3 exomes
AF:
AC:
1
AN:
251278
Hom.:
AF XY:
AC XY:
0
AN XY:
135812
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461780Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0AN XY: 727188
GnomAD4 exome
AF:
AC:
2
AN:
1461780
Hom.:
Cov.:
40
AF XY:
AC XY:
0
AN XY:
727188
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ExAC
AF:
AC:
1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial complex III deficiency nuclear type 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 08, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 11, 2021 | Published functional studies demonstrate a damaging effect; the L215F variant significantly reduced NADH-cytochrome c reductase activity (Gaignard et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23910460, 25914718, 27074787) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at L215 (P = 0.0722);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at