rs8139305

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-50523636-G-A
• chr22-50523636-G-C
• chr22-50523636-G-T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:11
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.776C>T	p.Ala259Val	missense	Exon 2 of 2	NP_005129.2	O43819
	NCAPH2	NM_152299.4	MANE Select	c.*261G>A		3_prime_UTR	Exon 20 of 20	NP_689512.2	Q6IBW4-1
	SCO2	NM_001169109.2		c.776C>T	p.Ala259Val	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>T	p.Ala259Val	missense	Exon 2 of 2	ENSP00000379046.4	O43819
	NCAPH2	ENST00000420993.7	TSL:1 MANE Select	c.*261G>A		3_prime_UTR	Exon 20 of 20	ENSP00000410088.2	Q6IBW4-1
	SCO2	ENST00000252785.3	TSL:2	c.776C>T	p.Ala259Val	missense	Exon 2 of 2	ENSP00000252785.3	O43819

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

GnomAD2 exomes AF: 0.00237 AC: 596 AN: 251188 AF XY: 0.00182

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 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

African (AFR) AF: 0.0316 AC: 1057 AN: 33478

American (AMR) AF: 0.00165 AC: 74 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

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

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5630

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1112006

Other (OTH) AF: 0.00171 AC: 103 AN: 60360

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

African (AFR) AF: 0.0303 AC: 1260 AN: 41564

American (AMR) AF: 0.00301 AC: 46 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00330 Hom.: 20

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.67
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.31	T
Sift4G	Benign	0.58	T
Polyphen		0.95	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
Mutation Taster		=85/15	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;