8-99892049-T-C

Variant names:

• chr8-99892049-T-C
• rs1130474
• NM_004374.4:c.-28A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004374.4(COX6C):​c.-28A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,522,390 control chromosomes in the GnomAD database, including 30,101 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 0.24 (5682 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24419 hom.)
• Consequence: COX6C NM_004374.4 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00002058
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 19 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX6C	NM_004374.4	c.-28A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	ENST00000520468.7	NP_004365.1
COX6C	NM_004374.4	c.-28A>G		5_prime_UTR_variant	Exon 2 of 4	ENST00000520468.7	NP_004365.1
COX6C	XM_017013020.2	c.-28A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4		XP_016868509.1
COX6C	XM_017013020.2	c.-28A>G		5_prime_UTR_variant	Exon 2 of 4		XP_016868509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX6C	ENST00000520468.7	c.-28A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	1	NM_004374.4	ENSP00000428895.1
COX6C	ENST00000520468.7	c.-28A>G		5_prime_UTR_variant	Exon 2 of 4	1	NM_004374.4	ENSP00000428895.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37213 AN: 152060 Hom.: 5662 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.185 AC: 41837 AN: 225632 AF XY: 0.180

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.181 AC: 248313 AN: 1370212 Hom.: 24419 Cov.: 21 AF XY: 0.179 AC XY: 122740 AN XY: 684746

African (AFR) AF: 0.446 AC: 13577 AN: 30470

American (AMR) AF: 0.164 AC: 6132 AN: 37416

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5238 AN: 24170

East Asian (EAS) AF: 0.126 AC: 4959 AN: 39214

South Asian (SAS) AF: 0.133 AC: 10679 AN: 80564

European-Finnish (FIN) AF: 0.149 AC: 7844 AN: 52478

Middle Eastern (MID) AF: 0.163 AC: 899 AN: 5524

European-Non Finnish (NFE) AF: 0.180 AC: 188138 AN: 1043484

Other (OTH) AF: 0.191 AC: 10847 AN: 56892

GnomAD4 genome AF: 0.245 AC: 37266 AN: 152178 Hom.: 5682 Cov.: 32 AF XY: 0.240 AC XY: 17889 AN XY: 74422

African (AFR) AF: 0.433 AC: 17941 AN: 41474

American (AMR) AF: 0.171 AC: 2616 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3472

East Asian (EAS) AF: 0.130 AC: 673 AN: 5186

South Asian (SAS) AF: 0.120 AC: 581 AN: 4830

European-Finnish (FIN) AF: 0.161 AC: 1704 AN: 10604

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12281 AN: 68004

Other (OTH) AF: 0.205 AC: 432 AN: 2112

Alfa AF: 0.200 Hom.: 4337

Bravo AF: 0.258

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.2
DANN	Benign	0.59
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0080
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

Other links and lift over

dbSNP: rs1130474; hg19: chr8-100904277; COSMIC: COSV52553630;