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:7
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005138.3. 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
	SCO2	NM_005138.3	MANE Select	c.268C>T	p.Arg90*	stop_gained	Exon 2 of 2	NP_005129.2	O43819
	NCAPH2	NM_152299.4	MANE Select	c.*769G>A		3_prime_UTR	Exon 20 of 20	NP_689512.2	Q6IBW4-1
	SCO2	NM_001169109.2		c.268C>T	p.Arg90*	stop_gained	Exon 2 of 2	NP_001162580.1	O43819

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCO2	ENST00000395693.8	TSL:1 MANE Select	c.268C>T	p.Arg90*	stop_gained	Exon 2 of 2	ENSP00000379046.4	O43819
	NCAPH2	ENST00000420993.7	TSL:1 MANE Select	c.*769G>A		3_prime_UTR	Exon 20 of 20	ENSP00000410088.2	Q6IBW4-1
	SCO2	ENST00000252785.3	TSL:2	c.268C>T	p.Arg90*	stop_gained	Exon 2 of 2	ENSP00000252785.3	O43819

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (4)
2	-	-	Myopia 6 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;