Genetic Variant CYC1:p.Leu39Leu (chr8-144095216-A-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001916.5(CYC1):c.117A>G(p.Leu39Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,048,700 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CYC1
NM_001916.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.34

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 8-144095216-A-G is Benign according to our data. Variant chr8-144095216-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1976625.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.34 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYC1	NM_001916.5 link	c.117A>G	p.Leu39Leu	synonymous_variant	Exon 1 of 7	ENST00000318911.5	NP_001907.3	P08574

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYC1	ENST00000318911.5 link	c.117A>G	p.Leu39Leu	synonymous_variant	Exon 1 of 7	1	NM_001916.5	ENSP00000317159.4		P08574
CYC1	ENST00000533444.1 link	n.178A>G		non_coding_transcript_exon_variant	Exon 1 of 6	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1048700

Hom.:

Cov.:

AF XY:

0.00000404

AC XY:

AN XY:

494736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21830

American (AMR)

AF:

0.00

AC:

AN:

7338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12808

East Asian (EAS)

AF:

0.00

AC:

AN:

23668

South Asian (SAS)

AF:

0.00

AC:

AN:

19118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2782

European-Non Finnish (NFE)

AF:

0.00000334

AC:

AN:

899322

Other (OTH)

AF:

0.00

AC:

AN:

41266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

-1.3

PromoterAI

-0.064

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over