Genetic Variant NM_004374.4:c.168C>T (chr8-99887565-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_004374.4(COX6C):c.168C>T(p.Tyr56Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,607,334 control chromosomes in the GnomAD database, including 33,408 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 6758 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26650 hom. )

Consequence

COX6C
NM_004374.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

28 publications found

Variant links:

Genes affected

COX6C (HGNC:2285): (cytochrome c oxidase subunit 6C) Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIc, which has 77% amino acid sequence identity with mouse subunit VIc. This gene is up-regulated in prostate cancer cells. A pseudogene has been found on chromosomes 16p12. [provided by RefSeq, Jul 2010]

COX6C links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP7

Synonymous conserved (PhyloP=1.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX6C	NM_004374.4 link	c.168C>T	p.Tyr56Tyr	synonymous_variant	Exon 3 of 4	ENST00000520468.7	NP_004365.1	P09669A0A024R9B7
COX6C	XM_017013020.2 link	c.168C>T	p.Tyr56Tyr	synonymous_variant	Exon 3 of 4		XP_016868509.1	P09669A0A024R9B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX6C	ENST00000520468.7 link	c.168C>T	p.Tyr56Tyr	synonymous_variant	Exon 3 of 4	1	NM_004374.4	ENSP00000428895.1		P09669

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39496

AN:

151810

Hom.:

6740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.129

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.194

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.214

GnomAD2 exomes

AF:

0.183

AC:

45194

AN:

246822

AF XY:

0.176

show subpopulations

Gnomad AFR exome

AF:

0.490

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.203

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.152

Gnomad NFE exome

AF:

0.175

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.182

AC:

264492

AN:

1455406

Hom.:

26650

Cov.:

AF XY:

0.179

AC XY:

129841

AN XY:

724000

show subpopulations

African (AFR)

AF:

0.499

AC:

16440

AN:

32942

American (AMR)

AF:

0.163

AC:

7138

AN:

43842

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

5457

AN:

25972

East Asian (EAS)

AF:

0.125

AC:

4939

AN:

39456

South Asian (SAS)

AF:

0.130

AC:

11045

AN:

85188

European-Finnish (FIN)

AF:

0.149

AC:

7911

AN:

53270

Middle Eastern (MID)

AF:

0.160

AC:

920

AN:

5748

European-Non Finnish (NFE)

AF:

0.180

AC:

199100

AN:

1108884

Other (OTH)

AF:

0.192

AC:

11542

AN:

60104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

9624

19247

28871

38494

48118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7132

14264

21396

28528

35660

<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:

0.260

AC:

39550

AN:

151928

Hom.:

6758

Cov.:

AF XY:

0.255

AC XY:

18973

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.488

AC:

20206

AN:

41424

American (AMR)

AF:

0.177

AC:

2705

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

728

AN:

3468

East Asian (EAS)

AF:

0.129

AC:

668

AN:

5172

South Asian (SAS)

AF:

0.119

AC:

574

AN:

4806

European-Finnish (FIN)

AF:

0.161

AC:

1699

AN:

10522

Middle Eastern (MID)

AF:

0.192

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.180

AC:

12232

AN:

67962

Other (OTH)

AF:

0.211

AC:

446

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1339

2678

4016

5355

6694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.255

Hom.:

4213

Bravo

AF:

0.275

Asia WGS

AF:

0.166

AC:

579

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.8

(source)

DANN

Benign

0.22

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over