rs778740017

Variant names:

• chr19-35651301-C-T
• rs778740017
• NM_001863.5:c.58C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001863.5(COX6B1):​c.58C>T​(p.Arg20Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COX6B1 NM_001863.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.05
• Publications: 13 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35651302-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16875.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 1.2921 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex IV deficiency, nuclear type 7, cytochrome-c oxidase deficiency disease, mitochondrial disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 19-35651301-C-T is Pathogenic according to our data. Variant chr19-35651301-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217745.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX6B1	NM_001863.5	c.58C>T	p.Arg20Cys	missense_variant	Exon 2 of 4	ENST00000649813.2	NP_001854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX6B1	ENST00000649813.2	c.58C>T	p.Arg20Cys	missense_variant	Exon 2 of 4		NM_001863.5	ENSP00000497926.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251476 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:2

Nov 05, 2019

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.93	.;.;.;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.28	D
PhyloP100		1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.5	D;.;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.027	D;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.89	P;P;P;P
Vest4		0.79
MutPred		0.91		Loss of disorder (P = 0.0357);Loss of disorder (P = 0.0357);Loss of disorder (P = 0.0357);Loss of disorder (P = 0.0357);
MVP		0.88
MPC		1.2
ClinPred		0.92	D
GERP RS		5.3
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs778740017; hg19: chr19-36142203; COSMIC: COSV55837949;