8-144095930-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001916.5(CYC1):c.227T>C(p.Met76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00513 in 1,608,370 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M76V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 25 hom. )

Consequence

CYC1
NM_001916.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 3.61

Publications

5 publications found

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]

CYC1 Gene-Disease associations (from GenCC):

mitochondrial complex III deficiency nuclear type 6
Inheritance: Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
mitochondrial complex III deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060787797).

BP6

Variant 8-144095930-T-C is Benign according to our data. Variant chr8-144095930-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 25 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYC1	NM_001916.5 link	c.227T>C	p.Met76Thr	missense_variant	Exon 2 of 7	ENST00000318911.5	NP_001907.3	P08574

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYC1	ENST00000318911.5 link	c.227T>C	p.Met76Thr	missense_variant	Exon 2 of 7	1	NM_001916.5	ENSP00000317159.4	P08574
CYC1	ENST00000533444.1 link	n.892T>C		non_coding_transcript_exon_variant	Exon 1 of 6	1
CYC1	ENST00000528618.1 link	n.445T>C		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00373

AC:

568

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00867

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00601

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00429

AC:

1060

AN:

247102

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.000499

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00867

Gnomad NFE exome

AF:

0.00706

Gnomad OTH exome

AF:

0.00345

GnomAD4 exome

AF:

0.00528

AC:

7688

AN:

1456148

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

3792

AN XY:

724668

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33472

American (AMR)

AF:

0.00116

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000557

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00774

AC:

372

AN:

48046

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00627

AC:

6967

AN:

1111836

Other (OTH)

AF:

0.00351

AC:

212

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

503

1006

1510

2013

2516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00373

AC:

568

AN:

152222

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

271

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41538

American (AMR)

AF:

0.00111

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00867

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00601

AC:

409

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00437

AC:

531

EpiCase

AF:

0.00600

EpiControl

AF:

0.00462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign