rs145100473

chr22-50524071-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005138.3(SCO2):c.341G>A(p.Arg114His) variant causes a missense change. The variant allele was found at a frequency of 0.000394 in 1,613,244 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (6 hom.)
• Consequence: SCO2 NM_005138.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2
• Conservation: PhyloP100: 3.65

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10600731).
• BP6: Variant 22-50524071-C-T is Benign according to our data. Variant chr22-50524071-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 50905.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCO2	NM_005138.3	c.341G>A	p.Arg114His	missense_variant	2/2	ENST00000395693.8
NCAPH2	NM_152299.4	c.*696C>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.341G>A	p.Arg114His	missense_variant	2/2	1	NM_005138.3	P1
NCAPH2	ENST00000420993.7	c.*696C>T		3_prime_UTR_variant	20/20	1	NM_152299.4	P4
	ENST00000608319.1	n.146C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000831 AC: 208 AN: 250450 Hom.: 1 AF XY: 0.000789 AC XY: 107 AN XY: 135664

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000354 AC: 517 AN: 1460952 Hom.: 6 Cov.: 73 AF XY: 0.000376 AC XY: 273 AN XY: 726792

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74460

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000895

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27581939, 25959673, 34426522, 23643385, 35457050, 28518168, 35328081, 32461654) -

Myopia 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.036	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.80
MVP		0.90
MPC		0.27
ClinPred		0.069	T
GERP RS		5.0
Varity_R		0.74
gMVP		0.64

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: rs145100473; hg19: chr22-50962500; COSMIC: COSV52688796; COSMIC: COSV52688796;