rs749838192

Positions:

• chr22-50524395-C-CTGAGTCACTGCTGCATGCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_005138.3(SCO2):​c.16_17insAGCATGCAGCAGTGACTCA​(p.Arg6fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,605,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: SCO2 NM_005138.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.0470

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]

ENSG00000272821 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PP5: Variant 22-50524395-C-CTGAGTCACTGCTGCATGCT is Pathogenic according to our data. Variant chr22-50524395-C-CTGAGTCACTGCTGCATGCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCO2	NM_005138.3	c.16_17insAGCATGCAGCAGTGACTCA	p.Arg6fs	frameshift_variant	2/2	ENST00000395693.8	NP_005129.2
NCAPH2	NM_152299.4	c.*1020_*1021insTGAGTCACTGCTGCATGCT		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.16_17insAGCATGCAGCAGTGACTCA	p.Arg6fs	frameshift_variant	2/2	1	NM_005138.3	ENSP00000379046.4
NCAPH2	ENST00000420993.7	c.*1020_*1021insTGAGTCACTGCTGCATGCT		3_prime_UTR_variant	20/20	1	NM_152299.4	ENSP00000410088.2

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000576 AC: 137 AN: 237888 Hom.: 0 AF XY: 0.000641 AC XY: 84 AN XY: 130968

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00785

Gnomad NFE exome AF: 0.0000648

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000343 AC: 498 AN: 1452934 Hom.: 0 Cov.: 34 AF XY: 0.000359 AC XY: 260 AN XY: 723238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000594 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2023	Reported with a second variant, phase unknown, in an infant with respiratory failure and distal contractures (PMID: 32668698); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20159436, 32668698, 36675121) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change creates a premature translational stop signal (p.Arg6Glnfs*82) in the SCO2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 261 amino acid(s) of the SCO2 protein. This variant is present in population databases (rs749838192, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with cardioencephalomyopathy (PMID: 20159436). This variant is also known as c.17INS19bp. ClinVar contains an entry for this variant (Variation ID: 222816). This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Gln53*) have been determined to be pathogenic (PMID: 10545952, 15210538, 19879173). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:2

Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_005138.2:c.16_17insAGCATGCAGCAGTGACTCA in the SCO2 gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The p.Arg6Glnfs*82 (NM_005138.2:c.16_17insAGCATGCAGCAGTGACTCA) variant has been detected in an patient with Early-Onset Cardioencephalomyopathy, in tans with c.418G>A. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 03, 2015	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Aug 26, 2022

- -

Myopia 6;C5399977:Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749838192; hg19: chr22-50962824;