22-50523649-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005138.3(SCO2):c.763C>A(p.Arg255=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,613,860 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0090 (71 hom.)
• Consequence: SCO2 NM_005138.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.606

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 22-50523649-G-T is Benign according to our data. Variant chr22-50523649-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139087.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=1}. Variant chr22-50523649-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.606 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCO2	NM_005138.3	c.763C>A	p.Arg255=	synonymous_variant	2/2	ENST00000395693.8
NCAPH2	NM_152299.4	c.*274G>T		3_prime_UTR_variant	20/20	ENST00000420993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCO2	ENST00000395693.8	c.763C>A	p.Arg255=	synonymous_variant	2/2	1	NM_005138.3	P1
NCAPH2	ENST00000420993.7	c.*274G>T		3_prime_UTR_variant	20/20	1	NM_152299.4	P4

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152210 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00567 AC: 1424 AN: 251258 Hom.: 9 AF XY: 0.00562 AC XY: 763 AN XY: 135862

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00899 AC: 13141 AN: 1461532 Hom.: 71 Cov.: 35 AF XY: 0.00881 AC XY: 6409 AN XY: 727074

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.00376

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00802

GnomAD4 genome AF: 0.00576 AC: 878 AN: 152328 Hom.: 4 Cov.: 34 AF XY: 0.00495 AC XY: 369 AN XY: 74478

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00779 Hom.: 0

Bravo AF: 0.00561

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00883

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCO2: BP4, BP7, BS1, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fatal Infantile Cardioencephalomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.2
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs112793292; hg19: chr22-50962078;