22-50523649-G-T

Variant names:

• chr22-50523649-G-T
• rs112793292
• NM_005138.3:c.763C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005138.3(SCO2):​c.763C>A​(p.Arg255Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,613,860 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0090 (71 hom.)
• Consequence: SCO2 NM_005138.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.606
• Publications: 6 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 22-50523649-G-T is Benign according to our data. Variant chr22-50523649-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139087.
• BP7: Synonymous conserved (PhyloP=0.606 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.763C>A	p.Arg255Arg	synonymous	Exon 2 of 2	NP_005129.2	O43819
	NCAPH2	NM_152299.4	MANE Select	c.*274G>T		3_prime_UTR	Exon 20 of 20	NP_689512.2	Q6IBW4-1
	SCO2	NM_001169109.2		c.763C>A	p.Arg255Arg	synonymous	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.763C>A	p.Arg255Arg	synonymous	Exon 2 of 2	ENSP00000379046.4	O43819
	NCAPH2	ENST00000420993.7	TSL:1 MANE Select	c.*274G>T		3_prime_UTR	Exon 20 of 20	ENSP00000410088.2	Q6IBW4-1
	SCO2	ENST00000252785.3	TSL:2	c.763C>A	p.Arg255Arg	synonymous	Exon 2 of 2	ENSP00000252785.3	O43819

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152210 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00567 AC: 1424 AN: 251258 AF XY: 0.00562

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00899 AC: 13141 AN: 1461532 Hom.: 71 Cov.: 35 AF XY: 0.00881 AC XY: 6409 AN XY: 727074

African (AFR) AF: 0.00146 AC: 49 AN: 33478

American (AMR) AF: 0.00253 AC: 113 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26136

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

South Asian (SAS) AF: 0.00197 AC: 170 AN: 86250

European-Finnish (FIN) AF: 0.00376 AC: 200 AN: 53176

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5696

European-Non Finnish (NFE) AF: 0.0108 AC: 12027 AN: 1112002

Other (OTH) AF: 0.00802 AC: 484 AN: 60372

GnomAD4 genome AF: 0.00576 AC: 878 AN: 152328 Hom.: 4 Cov.: 34 AF XY: 0.00495 AC XY: 369 AN XY: 74478

African (AFR) AF: 0.00154 AC: 64 AN: 41574

American (AMR) AF: 0.00333 AC: 51 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 712 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00802 Hom.: 1

Bravo AF: 0.00561

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.00883

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (1)
-	1	-	Fatal Infantile Cardioencephalomyopathy (1)
-	1	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs112793292; hg19: chr22-50962078;