rs74315512

Variant names:

• chr22-50524144-G-A
• rs74315512
• NM_005138.3:c.268C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005138.3(SCO2):​c.268C>T​(p.Arg90*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,438 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R90R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SCO2 NM_005138.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.34
• Publications: 7 publications found

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

Our verdict: Pathogenic. The variant received 16 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 31 pathogenic variants in the truncated region.
• PP5: Variant 22-50524144-G-A is Pathogenic according to our data. Variant chr22-50524144-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCO2	NM_005138.3	c.268C>T	p.Arg90*	stop_gained	Exon 2 of 2	ENST00000395693.8	NP_005129.2
NCAPH2	NM_152299.4	c.*769G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000420993.7	NP_689512.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCO2	ENST00000395693.8	c.268C>T	p.Arg90*	stop_gained	Exon 2 of 2	1	NM_005138.3	ENSP00000379046.4
NCAPH2	ENST00000420993.7	c.*769G>A		3_prime_UTR_variant	Exon 20 of 20	1	NM_152299.4	ENSP00000410088.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246876 AF XY: 0.0000149

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: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459438 Hom.: 0 Cov.: 74 AF XY: 0.00000964 AC XY: 7 AN XY: 726122

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000496 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 Pathogenic:3

Mar 22, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 26, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

• The p.Arg90* variant in the SCO2 gene has previously been reported in trans with a pathogenic variant (p.E140K) in two siblings affected with cytochrome c oxidase deficiency, consistent with autosomal recessive inheritance (Jaksch et al., 2000). • This variant has been identified in 3/111,340 (0.0027%) European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. • The p.Arg90* variant leads to a premature stop codon in exon 1 of 1 coding exons, removing 227 amino acids and a majority of the thioredoxim domain, resulting in a truncated protein. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg90* variant as likely pathogenic for cytochrome c oxidase deficiency syndrome in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2; PM3] -

Nov 20, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopia 6 Pathogenic:2

Nov 03, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>T;p.(Arg90*) variant creates a premature translational stop signal in the SCO2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5682; PMID: 10749987; PMID:33171185; PMID:23719228) - PS4. The variant is present at low allele frequencies population databases (rs74315512 – gnomAD 0.0001620%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Mar 25, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PVS1, PM2 -

not provided Pathogenic:1

May 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg90*) in the SCO2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the SCO2 protein. This variant is present in population databases (rs74315512, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive cardioencephalomyopathy (PMID: 10749987). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5682). This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Glu140Lys) have been determined to be pathogenic (PMID: 10545952, 15210538, 16765077, 23719228). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.0087
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		1.3
Vest4		0.84
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	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: rs74315512; hg19: chr22-50962573;