rs10420252

Variant names:

• chr19-35648270-G-A
• rs10420252
• ENST00000938367.1:c.-145G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000938367.1(COX6B1):​c.-145G>A variant causes a 5 prime UTR 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 ENST00000938367.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.66
• Publications: 7 publications found

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]

COX6B1 Gene-Disease associations (from GenCC):

• mitochondrial complex IV deficiency, nuclear type 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000938367.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX6B1	NM_001863.5	MANE Select	c.-145G>A		upstream_gene	N/A	NP_001854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX6B1	ENST00000938367.1		c.-145G>A		5_prime_UTR	Exon 1 of 4	ENSP00000608426.1
	COX6B1	ENST00000649813.2	MANE Select	c.-145G>A		upstream_gene	N/A	ENSP00000497926.1
	COX6B1	ENST00000938371.1		c.-145G>A		upstream_gene	N/A	ENSP00000608430.1

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.177 AC: 22 AN: 124

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.113 AC: 30 AN: 266

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.111 AC: 56 AN: 506

Other (OTH) AF: 0.0455 AC: 1 AN: 22

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

African (AFR) AF: 0.0936 AC: 3888 AN: 41558

American (AMR) AF: 0.139 AC: 2128 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.136 AC: 704 AN: 5164

South Asian (SAS) AF: 0.0952 AC: 459 AN: 4820

European-Finnish (FIN) AF: 0.113 AC: 1198 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0864 AC: 5878 AN: 68016

Other (OTH) AF: 0.0918 AC: 194 AN: 2114

Alfa AF: 0.0888 Hom.: 821

Bravo AF: 0.101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		1.7
PromoterAI		0.0056	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10420252; hg19: chr19-36139172;