22-50523636-G-T

Variant names:

• chr22-50523636-G-T
• rs8139305
• NM_005138.3:c.776C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005138.3(SCO2):​c.776C>A​(p.Ala259Glu) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• Publications: 13 publications found

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

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=0.18871227).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCO2	NM_005138.3	MANE Select	c.776C>A	p.Ala259Glu	missense	Exon 2 of 2	NP_005129.2	O43819
	NCAPH2	NM_152299.4	MANE Select	c.*261G>T		3_prime_UTR	Exon 20 of 20	NP_689512.2	Q6IBW4-1
	SCO2	NM_001169109.2		c.776C>A	p.Ala259Glu	missense	Exon 2 of 2	NP_001162580.1	O43819

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCO2	ENST00000395693.8	TSL:1 MANE Select	c.776C>A	p.Ala259Glu	missense	Exon 2 of 2	ENSP00000379046.4	O43819
	NCAPH2	ENST00000420993.7	TSL:1 MANE Select	c.*261G>T		3_prime_UTR	Exon 20 of 20	ENSP00000410088.2	Q6IBW4-1
	SCO2	ENST00000252785.3	TSL:2	c.776C>A	p.Ala259Glu	missense	Exon 2 of 2	ENSP00000252785.3	O43819

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251188 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000137 AC: 2 AN: 1461414 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727016

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00000276 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	10
DANN	Benign	0.79
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.67
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.26
Sift	Benign	0.85	T
Sift4G	Benign	0.84	T
Polyphen		0.89	P
Vest4		0.29
MutPred		0.41		Gain of disorder (P = 0.0251)
MVP		0.81
MPC		0.040
ClinPred		0.077	T
GERP RS		1.7
Varity_R		0.063
gMVP		0.42
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs8139305; hg19: chr22-50962065;