17-10697492-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004589.4(SCO1):c.16C>G(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,613,454 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (41 hom.)
• Consequence: SCO1 NM_004589.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: -0.540

Genes affected

SCO1 (HGNC:10603): (synthesis of cytochrome C oxidase 1) Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog to the yeast SCO1 gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040917993).
• BP6: Variant 17-10697492-G-C is Benign according to our data. Variant chr17-10697492-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139078.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=4, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00379 (578/152342) while in subpopulation NFE AF= 0.00639 (435/68026). AF 95% confidence interval is 0.0059. There are 3 homozygotes in gnomad4. There are 288 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCO1	NM_004589.4	c.16C>G	p.Leu6Val	missense_variant	1/6	ENST00000255390.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCO1	ENST00000255390.10	c.16C>G	p.Leu6Val	missense_variant	1/6	1	NM_004589.4	P1

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152224 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00363 AC: 902 AN: 248192 Hom.: 2 AF XY: 0.00368 AC XY: 497 AN XY: 134936

Gnomad AFR exome AF: 0.00140

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.000852

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00651

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00629 AC: 9190 AN: 1461112 Hom.: 41 Cov.: 31 AF XY: 0.00619 AC XY: 4500 AN XY: 726826

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.000416

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00379 AC: 578 AN: 152342 Hom.: 3 Cov.: 33 AF XY: 0.00387 AC XY: 288 AN XY: 74498

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00639

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00520 Hom.: 0

Bravo AF: 0.00399

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00362 AC: 439

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00617

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SCO1: BP4, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SCO1 p.Leu6Val variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs61753148), ClinVar (reported as benign, likely benign and uncertain significance), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 1015 of 279580 chromosomes (2 homozygous) at a frequency of 0.00363 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 818 of 126916 chromosomes (freq: 0.006445), Other in 25 of 7176 chromosomes (freq: 0.003484), Latino in 93 of 35346 chromosomes (freq: 0.002631), African in 39 of 24464 chromosomes (freq: 0.001594), South Asian in 26 of 30522 chromosomes (freq: 0.000852), European (Finnish) in 10 of 25074 chromosomes (freq: 0.000399), East Asian in 3 of 19798 chromosomes (freq: 0.000152), and Ashkenazi Jewish in 1 of 10284 chromosomes (freq: 0.000097). The p.Leu6 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2023	Variant summary: SCO1 c.16C>G (p.Leu6Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 248192 control chromosomes in the gnomAD database, including 2 homozygotes. c.16C>G has been reported in the literature in individuals affected with Mitochondrial Complex 4 Deficiency without evidence for causality (e.g. McCormack_2016, Kumps_2021). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial Complex 4 Deficiency, Nuclear Type 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33340101; Book Chapter: doi.org/10.1016/B978-0-12-800877-5.00021-8). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	2.2
Dann	Benign	0.96
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.41	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.52	N;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.0010	B;.
Vest4		0.055
MVP		0.46
MPC		0.14
ClinPred		0.067	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.25

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: rs61753148; hg19: chr17-10600809;