17-10697492-G-C

Position:

chr17-10697492-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 41 hom. )

Consequence

SCO1
NM_004589.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: -0.540

Variant links:

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]

SCO1 links:

SCO1 (HGNC:):

SCO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=2, Uncertain_significance=4, 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 GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCO1	NM_004589.4 linkuse as main transcript	c.16C>G	p.Leu6Val	missense_variant	1/6	ENST00000255390.10	NP_004580.1	O75880

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCO1	ENST00000255390.10 linkuse as main transcript	c.16C>G	p.Leu6Val	missense_variant	1/6	1	NM_004589.4	ENSP00000255390.5		O75880

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

578

AN:

152224

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00368

AC XY:

497

AN XY:

134936

show subpopulations

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.:

Cov.:

AF XY:

0.00619

AC XY:

4500

AN XY:

726826

show subpopulations

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.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74498

show subpopulations

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.:

Bravo

AF:

0.00399

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00362

AC:

439

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00665

EpiControl

AF:

0.00617

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
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	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCO1: BP4, BS2 -

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:1Benign: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

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

LIST_S2

Benign

0.41

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.33

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over