Genetic Variant NM_005138.3:c.776C>G (chr22-50523636-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005138.3(SCO2):c.776C>G(p.Ala259Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A259T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCO2
NM_005138.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.669

Publications

13 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24640235).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCO2	NM_005138.3	MANE Select	c.776C>G	p.Ala259Gly	missense	Exon 2 of 2	NP_005129.2	O43819
NCAPH2	NM_152299.4	MANE Select	c.*261G>C		3_prime_UTR	Exon 20 of 20	NP_689512.2	Q6IBW4-1
SCO2	NM_001169109.2		c.776C>G	p.Ala259Gly	missense	Exon 2 of 2	NP_001162580.1	O43819

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCO2	ENST00000395693.8	TSL:1 MANE Select	c.776C>G	p.Ala259Gly	missense	Exon 2 of 2	ENSP00000379046.4	O43819
NCAPH2	ENST00000420993.7	TSL:1 MANE Select	c.*261G>C		3_prime_UTR	Exon 20 of 20	ENSP00000410088.2	Q6IBW4-1
SCO2	ENST00000252785.3	TSL:2	c.776C>G	p.Ala259Gly	missense	Exon 2 of 2	ENSP00000252785.3	O43819

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.77

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.34

M_CAP

Benign

0.078

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.0

PhyloP100

0.67

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Benign

0.35

Sift4G

Benign

0.50

Polyphen

0.70

Vest4

0.41

MutPred

0.26

Gain of disorder (P = 0.0999)

MVP

0.80

MPC

0.037

ClinPred

0.17

GERP RS

1.7

Varity_R

0.054

gMVP

0.32

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over