rs10420252

Variant names:

• chr19-35648270-G-A
• rs10420252
• NM_001863.5:c.-145G>A

Variant summary

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

The NM_001863.5(COX6B1):​c.-145G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 153,178 control chromosomes in the GnomAD database, including 785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (776 hom., cov: 32)
  • Exomes 𝑓: 0.12 (9 hom.)
• Consequence: COX6B1 NM_001863.5 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.66

Genes affected

COX6B1 (HGNC:2280): (cytochrome c oxidase subunit 6B1) Cytochrome c oxidase (COX), 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 VIb. Mutations in this gene are associated with severe infantile encephalomyopathy. Three pseudogenes COX6BP-1, COX6BP-2 and COX6BP-3 have been found on chromosomes 7, 17 and 22q13.1-13.2, respectively. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-35648270-G-A is Benign according to our data. Variant chr19-35648270-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX6B1	NM_001863.5	c.-145G>A		upstream_gene_variant		ENST00000649813.2	NP_001854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX6B1	ENST00000649813.2	c.-145G>A		upstream_gene_variant			NM_001863.5	ENSP00000497926.1

Frequencies

GnomAD3 genomes AF: 0.0971 AC: 14778 AN: 152138 Hom.: 773 Cov.: 32

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0951

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0864

Gnomad OTH AF: 0.0918

GnomAD4 exome AF: 0.119 AC: 110 AN: 922 Hom.: 9 Cov.: 0 AF XY: 0.124 AC XY: 71 AN XY: 574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.177

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.0455

GnomAD4 genome AF: 0.0972 AC: 14799 AN: 152256 Hom.: 776 Cov.: 32 AF XY: 0.0993 AC XY: 7393 AN XY: 74424

Gnomad4 AFR AF: 0.0936

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.0952

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.0864

Gnomad4 OTH AF: 0.0918

Alfa AF: 0.0862 Hom.: 589

Bravo AF: 0.101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	-0.64
CADD	Benign	13
DANN	Benign	0.90

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

LitVar

Other links and lift over

dbSNP: rs10420252; hg19: chr19-36139172;