rs144257411

Positions:

• chr8-144095930-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 14/21 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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (25 hom.)
• Consequence: CYC1 NM_001916.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 3.61

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 235356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYC1	NM_001916.5	c.227T>C	p.Met76Thr	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.227T>C	p.Met76Thr	missense_variant	2/7	1	NM_001916.5	ENSP00000317159	P1
CYC1	ENST00000533444.1	n.892T>C		non_coding_transcript_exon_variant	1/6	1
CYC1	ENST00000528618.1	n.445T>C		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152104 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00429 AC: 1060 AN: 247102 Hom.: 3 AF XY: 0.00432 AC XY: 579 AN XY: 134054

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 SAS exome AF: 0.000523

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.: 25 Cov.: 41 AF XY: 0.00523 AC XY: 3792 AN XY: 724668

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00774

Gnomad4 NFE exome AF: 0.00627

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74434

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00594 Hom.: 4

Bravo AF: 0.00314

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00437 AC: 531

EpiCase AF: 0.00600

EpiControl AF: 0.00462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CYC1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.45
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.067	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.041
Sift	Benign	0.20	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.037
MVP		0.28
MPC		0.32
ClinPred		0.0042	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144257411; hg19: chr8-145150833;