rs80358232

Positions:

• chr22-50523738-G-A
• chr22-50523738-G-C
• chr22-50523738-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005138.3(SCO2):​c.674C>T​(p.Ser225Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SCO2 NM_005138.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.16

Genes affected

SCO2 (HGNC:10604): (synthesis of cytochrome C oxidase 2) Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. Human COX is a multimeric protein complex that requires several assembly factors; this gene encodes one of the COX assembly factors. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6. [provided by RefSeq, Oct 2014]

NCAPH2 (HGNC:25071): (non-SMC condensin II complex subunit H2) This gene encodes one of the non-SMC subunits of the condensin II complex. This complex plays an essential role in mitotic chromosome assembly. Alternate splicing of this gene results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Thioredoxin (size 174) in uniprot entity SCO2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005138.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 22-50523738-G-A is Pathogenic according to our data. Variant chr22-50523738-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5679.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCO2	NM_005138.3	c.674C>T	p.Ser225Phe	missense_variant	2/2	ENST00000395693.8	NP_005129.2
NCAPH2	NM_152299.4	c.*363G>A		3_prime_UTR_variant	20/20	ENST00000420993.7	NP_689512.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCO2	ENST00000395693.8	c.674C>T	p.Ser225Phe	missense_variant	2/2	1	NM_005138.3	ENSP00000379046	P1
NCAPH2	ENST00000420993.7	c.*363G>A		3_prime_UTR_variant	20/20	1	NM_152299.4	ENSP00000410088	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.89
MutPred		0.94		Loss of disorder (P = 0.0897);Loss of disorder (P = 0.0897);Loss of disorder (P = 0.0897);Loss of disorder (P = 0.0897);
MVP		0.94
MPC		0.27
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.73

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: rs80358232; hg19: chr22-50962167; COSMIC: COSV99329636; COSMIC: COSV99329636;