rs35555197

Variant names:

• chr6-107245583-C-T
• rs35555197
• NM_020381.4:c.667G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 6.21
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• coenzyme Q10 deficiency, primary, 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome with nephrotic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028089583).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020381.4. 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
	PDSS2	NM_020381.4	MANE Select	c.667G>A	p.Val223Ile	missense	Exon 4 of 8	NP_065114.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS2	ENST00000369037.9	TSL:1 MANE Select	c.667G>A	p.Val223Ile	missense	Exon 4 of 8	ENSP00000358033.4	Q86YH6-1
	PDSS2	ENST00000900080.1		c.667G>A	p.Val223Ile	missense	Exon 4 of 9	ENSP00000570139.1
	PDSS2	ENST00000962908.1		c.532G>A	p.Val178Ile	missense	Exon 3 of 8	ENSP00000632967.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 151946 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00126 AC: 310 AN: 246528 AF XY: 0.00129

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 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.: 2 Cov.: 27 AF XY: 0.00153 AC XY: 1099 AN XY: 718472

African (AFR) AF: 0.000151 AC: 5 AN: 33150

American (AMR) AF: 0.000158 AC: 7 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 83538

European-Finnish (FIN) AF: 0.00136 AC: 72 AN: 53024

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5634

European-Non Finnish (NFE) AF: 0.00196 AC: 2157 AN: 1099112

Other (OTH) AF: 0.00114 AC: 68 AN: 59658

GnomAD4 genome AF: 0.00120 AC: 183 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74204

African (AFR) AF: 0.000314 AC: 13 AN: 41362

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00152 Hom.: 2

Bravo AF: 0.00102

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00155 AC: 188

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	2	-	Coenzyme Q10 deficiency, primary, 3 (2)
-	1	-	Kidney disorder (1)
-	1	-	not specified (1)
-	-	1	PDSS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.21
Sift	Benign	0.22	T
Sift4G	Benign	0.19	T
Polyphen		0.97	D
Vest4		0.45
MVP		0.58
MPC		0.39
ClinPred		0.10	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.44
Mutation Taster		=74/26	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: rs35555197; hg19: chr6-107566787;