chr22-50523624-C-T

Position:

chr22-50523624-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005138.3(SCO2):c.788G>A(p.Ser263Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,200 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 (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCO2
NM_005138.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95

Variant links:

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]

SCO2 links:

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]

NCAPH2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22613597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCO2	NM_005138.3 linkuse as main transcript	c.788G>A	p.Ser263Asn	missense_variant	2/2	ENST00000395693.8	NP_005129.2
NCAPH2	NM_152299.4 linkuse as main transcript	c.*249C>T		3_prime_UTR_variant	20/20	ENST00000420993.7	NP_689512.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCO2	ENST00000395693.8 linkuse as main transcript	c.788G>A	p.Ser263Asn	missense_variant	2/2	1	NM_005138.3	ENSP00000379046	P1
NCAPH2	ENST00000420993.7 linkuse as main transcript	c.*249C>T		3_prime_UTR_variant	20/20	1	NM_152299.4	ENSP00000410088	P4	Q6IBW4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251026

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2021

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. 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. This variant has not been reported in the literature in individuals affected with SCO2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 263 of the SCO2 protein (p.Ser263Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.43

T;T;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.50

.;T;.;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.7

L;L;L;L

MutationTaster

Benign

0.93

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.39

N;N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.016

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

0.028

B;B;B;B

Vest4

0.45

MutPred

0.29

Loss of phosphorylation at S263 (P = 0.0348);Loss of phosphorylation at S263 (P = 0.0348);Loss of phosphorylation at S263 (P = 0.0348);Loss of phosphorylation at S263 (P = 0.0348);

MVP

0.79

MPC

0.058

ClinPred

0.20

GERP RS

4.1

Varity_R

0.18

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over