rs587777042

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

Scores

11
7
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.73
Variant links:
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
CYC1NM_001916.5 linkuse as main transcriptc.643C>T p.Leu215Phe missense_variant 5/7 ENST00000318911.5 NP_001907.3 P08574

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYC1ENST00000318911.5 linkuse as main transcriptc.643C>T p.Leu215Phe missense_variant 5/71 NM_001916.5 ENSP00000317159.4 P08574
CYC1ENST00000533444.1 linkuse as main transcriptn.1308C>T non_coding_transcript_exon_variant 4/61
CYC1ENST00000525122.1 linkuse as main transcriptn.271C>T non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251278
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135812
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461780
Hom.:
0
Cov.:
40
AF XY:
0.00
AC XY:
0
AN XY:
727188
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
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 providedliterature onlyOMIMAug 08, 2013- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 11, 2021Published 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.98
MutPred
0.86
Gain of catalytic residue at L215 (P = 0.0722);
MVP
0.71
MPC
0.96
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.97
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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: rs587777042; hg19: chr8-145151518; API