NM_001863.5:c.42C>T

Variant names:

• chr19-35651285-C-T
• rs7991
• NM_001863.5:c.42C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001863.5(COX6B1):​c.42C>T​(p.Thr14Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 1,613,176 control chromosomes in the GnomAD database, including 9,699 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1610 hom., cov: 31)
  • Exomes 𝑓: 0.094 (8089 hom.)
• Consequence: COX6B1 NM_001863.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.40
• Publications: 17 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 19-35651285-C-T is Benign according to our data. Variant chr19-35651285-C-T is described in ClinVar as Benign. ClinVar VariationId is 137022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001863.5. 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.42C>T	p.Thr14Thr	synonymous	Exon 2 of 4	NP_001854.1	P14854

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX6B1	ENST00000649813.2	MANE Select	c.42C>T	p.Thr14Thr	synonymous	Exon 2 of 4	ENSP00000497926.1	P14854
	COX6B1	ENST00000938371.1		c.42C>T	p.Thr14Thr	synonymous	Exon 2 of 5	ENSP00000608430.1
	COX6B1	ENST00000392201.1	TSL:3	c.42C>T	p.Thr14Thr	synonymous	Exon 2 of 4	ENSP00000376037.2	P14854

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19940 AN: 151912 Hom.: 1599 Cov.: 31

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.122 AC: 30642 AN: 251458 AF XY: 0.118

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.0613

Gnomad EAS exome AF: 0.282

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.0771

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0936 AC: 136708 AN: 1461146 Hom.: 8089 Cov.: 32 AF XY: 0.0936 AC XY: 68008 AN XY: 726928

African (AFR) AF: 0.212 AC: 7102 AN: 33434

American (AMR) AF: 0.147 AC: 6573 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0601 AC: 1570 AN: 26134

East Asian (EAS) AF: 0.281 AC: 11155 AN: 39680

South Asian (SAS) AF: 0.129 AC: 11113 AN: 86226

European-Finnish (FIN) AF: 0.131 AC: 6971 AN: 53400

Middle Eastern (MID) AF: 0.0959 AC: 553 AN: 5768

European-Non Finnish (NFE) AF: 0.0769 AC: 85428 AN: 1111442

Other (OTH) AF: 0.103 AC: 6243 AN: 60344

GnomAD4 genome AF: 0.131 AC: 19980 AN: 152030 Hom.: 1610 Cov.: 31 AF XY: 0.136 AC XY: 10096 AN XY: 74310

African (AFR) AF: 0.208 AC: 8613 AN: 41440

American (AMR) AF: 0.136 AC: 2074 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.290 AC: 1495 AN: 5154

South Asian (SAS) AF: 0.142 AC: 684 AN: 4812

European-Finnish (FIN) AF: 0.132 AC: 1394 AN: 10574

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5247 AN: 67980

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.0935 Hom.: 846

Bravo AF: 0.135

Asia WGS AF: 0.215 AC: 745 AN: 3478

EpiCase AF: 0.0726

EpiControl AF: 0.0728

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	COX6B1-related disorder (1)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.8
DANN	Benign	0.61
PhyloP100		-1.4
PromoterAI		-0.020	Neutral
Mutation Taster		=98/2	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: rs7991; hg19: chr19-36142187; COSMIC: COSV55837491;