rs8139305

chr22-50523636-G-Achr22-50523636-G-Cchr22-50523636-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005138.3(SCO2):c.776C>T(p.Ala259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,613,760 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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: 𝑓 0.0087 (20 hom., cov: 34)
  • Exomes 𝑓: 0.00090 (15 hom.)
• Consequence: SCO2 NM_005138.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.669

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005732119).
• BP6: Variant 22-50523636-G-A is Benign according to our data. Variant chr22-50523636-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00871 (1327/152346) while in subpopulation AFR AF= 0.0303 (1260/41564). AF 95% confidence interval is 0.0289. There are 20 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCO2	NM_005138.3	c.776C>T	p.Ala259Val	missense_variant	2/2	ENST00000395693.8
NCAPH2	NM_152299.4	c.*261G>A		3_prime_UTR_variant	20/20	ENST00000420993.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCO2	ENST00000395693.8	c.776C>T	p.Ala259Val	missense_variant	2/2	1	NM_005138.3	P1
NCAPH2	ENST00000420993.7	c.*261G>A		3_prime_UTR_variant	20/20	1	NM_152299.4	P4

Frequencies

GnomAD3 genomes AF: 0.00872 AC: 1327 AN: 152228 Hom.: 20 Cov.: 34

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00237 AC: 596 AN: 251188 Hom.: 9 AF XY: 0.00182 AC XY: 247 AN XY: 135854

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000897 AC: 1311 AN: 1461414 Hom.: 15 Cov.: 34 AF XY: 0.000776 AC XY: 564 AN XY: 727016

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00871 AC: 1327 AN: 152346 Hom.: 20 Cov.: 34 AF XY: 0.00822 AC XY: 612 AN XY: 74494

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00138 Hom.: 4

Bravo AF: 0.00974

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00290 AC: 352

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 23643385) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SCO2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2016	- -

Mitochondrial complex IV deficiency, nuclear type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Mitochondrial DNA depletion syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Fatal Infantile Cardioencephalomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	16
Dann	Benign	0.92
DEOGEN2	Uncertain	0.50	D;D;D;D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0057	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.97	L;L;L;L
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.95	P;P;P;P
Vest4		0.72
MVP		0.81
MPC		0.035
ClinPred		0.0033	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.35

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: rs8139305; hg19: chr22-50962065;