8-144095110-C-T

Variant names:

• chr8-144095110-C-T
• rs548702965
• NM_001916.5:c.11C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001916.5(CYC1):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,210,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CYC1 NM_001916.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

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]

CYC1 Gene-Disease associations (from GenCC):

• mitochondrial complex III deficiency nuclear type 6

  Inheritance: AR, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14914957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001916.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYC1	NM_001916.5	MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 7	NP_001907.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYC1	ENST00000318911.5	TSL:1 MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 7	ENSP00000317159.4	P08574
	CYC1	ENST00000533444.1	TSL:1	n.72C>T		non_coding_transcript_exon	Exon 1 of 6
	CYC1	ENST00000876792.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 8	ENSP00000546851.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000680 AC: 72 AN: 1058382 Hom.: 0 Cov.: 31 AF XY: 0.0000700 AC XY: 35 AN XY: 499708

African (AFR) AF: 0.00 AC: 0 AN: 22018

American (AMR) AF: 0.00 AC: 0 AN: 7560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13104

East Asian (EAS) AF: 0.00 AC: 0 AN: 24286

South Asian (SAS) AF: 0.00238 AC: 46 AN: 19332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22468

Middle Eastern (MID) AF: 0.000982 AC: 3 AN: 3056

European-Non Finnish (NFE) AF: 0.0000199 AC: 18 AN: 904732

Other (OTH) AF: 0.000120 AC: 5 AN: 41826

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151938 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

Asia WGS AF: 0.00177 AC: 6 AN: 3398

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial complex III deficiency nuclear type 6 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.080	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.98	D
Vest4		0.40
MVP		0.27
MPC		0.55
ClinPred		0.67	D
GERP RS		3.3
PromoterAI		-0.0029	Neutral
Varity_R		0.20
gMVP		0.48
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs548702965; hg19: chr8-145150013;