22-50523625-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_005138.3(SCO2):c.787A>G(p.Ser263Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S263N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SCO2 NM_005138.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.880

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3514366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCO2	NM_005138.3	c.787A>G	p.Ser263Gly	missense_variant	2/2	ENST00000395693.8
NCAPH2	NM_152299.4	c.*250T>C		3_prime_UTR_variant	20/20	ENST00000420993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCO2	ENST00000395693.8	c.787A>G	p.Ser263Gly	missense_variant	2/2	1	NM_005138.3	P1
NCAPH2	ENST00000420993.7	c.*250T>C		3_prime_UTR_variant	20/20	1	NM_152299.4	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251014 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135804

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461198 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 726918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 263 of the SCO2 protein (p.Ser263Gly). This variant is present in population databases (rs748180870, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SCO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1518963). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.00059	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Uncertain	0.70	D;D;D;D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.63	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.3	L;L;L;L
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.68	P;P;P;P
Vest4		0.41
MutPred		0.32		Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);
MVP		0.82
MPC		0.062
ClinPred		0.24	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.40

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: rs748180870; hg19: chr22-50962054;