rs35555197

Positions:

chr6-107245583-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_020381.4(PDSS2):c.667G>A(p.Val223Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,595,666 control chromosomes in the GnomAD database, including 2 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 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

PDSS2
NM_020381.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

PDSS2 (HGNC:23041): (decaprenyl diphosphate synthase subunit 2) The protein encoded by this gene is an enzyme that synthesizes the prenyl side-chain of coenzyme Q, or ubiquinone, one of the key elements in the respiratory chain. The gene product catalyzes the formation of all trans-polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains, the first step in coenzyme Q biosynthesis. Defects in this gene are a cause of coenzyme Q10 deficiency.[provided by RefSeq, Oct 2009]

PDSS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028089583).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0012 (183/151946) while in subpopulation NFE AF= 0.00221 (150/68008). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDSS2	NM_020381.4 linkuse as main transcript	c.667G>A	p.Val223Ile	missense_variant	4/8	ENST00000369037.9	NP_065114.3	Q86YH6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDSS2	ENST00000369037.9 linkuse as main transcript	c.667G>A	p.Val223Ile	missense_variant	4/8	1	NM_020381.4	ENSP00000358033.4		Q86YH6-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00126

AC:

310

AN:

246528

Hom.:

AF XY:

0.00129

AC XY:

172

AN XY:

133260

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00247

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00160

AC:

2311

AN:

1443720

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1099

AN XY:

718472

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00136

Gnomad4 NFE exome

AF:

0.00196

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

151946

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00161

Gnomad4 NFE

AF:

0.00221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00155

AC:

188

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Coenzyme Q10 deficiency, primary, 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 21, 2023

Variant summary: PDSS2 c.667G>A (p.Val223Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 246528 control chromosomes (gnomAD). To our knowledge, no occurrence of c.667G>A in individuals affected with Coenzyme Q10 Deficiency, Primary, 3 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Kidney disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

PDSS2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

M_CAP

Benign

0.019

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.67

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Benign

0.19

Polyphen

0.97

Vest4

0.45

MVP

0.58

MPC

0.39

ClinPred

0.10

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.44

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