8-144095929-A-G

Position:

• chr8-144095929-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001916.5(CYC1):​c.226A>G​(p.Met76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,608,544 control chromosomes in the GnomAD database, including 793,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.96 (70747 hom., cov: 31)
  • Exomes 𝑓: 1.0 (722547 hom.)
• Consequence: CYC1 NM_001916.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.769

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4343906E-7).
• BP6: Variant 8-144095929-A-G is Benign according to our data. Variant chr8-144095929-A-G is described in ClinVar as [Benign]. Clinvar id is 1255439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYC1	NM_001916.5	c.226A>G	p.Met76Val	missense_variant	2/7	ENST00000318911.5	NP_001907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYC1	ENST00000318911.5	c.226A>G	p.Met76Val	missense_variant	2/7	1	NM_001916.5	ENSP00000317159.4
CYC1	ENST00000533444.1	n.891A>G		non_coding_transcript_exon_variant	1/6	1
CYC1	ENST00000528618.1	n.444A>G		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.962 AC: 146346 AN: 152088 Hom.: 70694 Cov.: 31

Gnomad AFR AF: 0.869

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.976

GnomAD3 exomes AF: 0.990 AC: 244725 AN: 247226 Hom.: 121276 AF XY: 0.992 AC XY: 133102 AN XY: 134132

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1450372 AN: 1456338 Hom.: 722547 Cov.: 75 AF XY: 0.996 AC XY: 722169 AN XY: 724784

Gnomad4 AFR exome AF: 0.861

Gnomad4 AMR exome AF: 0.992

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.991

GnomAD4 genome AF: 0.962 AC: 146458 AN: 152206 Hom.: 70747 Cov.: 31 AF XY: 0.964 AC XY: 71700 AN XY: 74414

Gnomad4 AFR AF: 0.869

Gnomad4 AMR AF: 0.986

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.976

Alfa AF: 0.992 Hom.: 77968

Bravo AF: 0.957

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.870 AC: 3830

ESP6500EA AF: 0.999 AC: 8589

ExAC AF: 0.988 AC: 119855

Asia WGS AF: 0.994 AC: 3456 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex III deficiency nuclear type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.4
DANN	Benign	0.37
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.0065	T
MetaRNN	Benign	5.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.018
Sift	Benign	0.66	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.28
ClinPred		0.000018	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs7820984; hg19: chr8-145150832; COSMIC: COSV59644891; COSMIC: COSV59644891;