NM_020381.4:c.11G>C

Variant names:

• chr6-107459275-C-G
• rs3734676
• NM_020381.4:c.11G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020381.4(PDSS2):​c.11G>C​(p.Arg4Pro) 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 1,613,900 control chromosomes in the GnomAD database, including 329 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (282 hom.)
• Consequence: PDSS2 NM_020381.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.356
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021348894).
• BP6: Variant 6-107459275-C-G is Benign according to our data. Variant chr6-107459275-C-G is described in ClinVar as Benign. ClinVar VariationId is 138690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS2	NM_020381.4	MANE Select	c.11G>C	p.Arg4Pro	missense	Exon 1 of 8	NP_065114.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS2	ENST00000369037.9	TSL:1 MANE Select	c.11G>C	p.Arg4Pro	missense	Exon 1 of 8	ENSP00000358033.4
	PDSS2	ENST00000369031.4	TSL:1	c.11G>C	p.Arg4Pro	missense	Exon 1 of 4	ENSP00000358027.4
	PDSS2	ENST00000900080.1		c.11G>C	p.Arg4Pro	missense	Exon 1 of 9	ENSP00000570139.1

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152086 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0155 AC: 3895 AN: 250640 AF XY: 0.0144

Gnomad AFR exome AF: 0.00483

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00947

GnomAD4 exome AF: 0.00576 AC: 8418 AN: 1461696 Hom.: 282 Cov.: 31 AF XY: 0.00571 AC XY: 4155 AN XY: 727144

African (AFR) AF: 0.00400 AC: 134 AN: 33476

American (AMR) AF: 0.0165 AC: 740 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.103 AC: 4092 AN: 39694

South Asian (SAS) AF: 0.00849 AC: 732 AN: 86238

European-Finnish (FIN) AF: 0.0232 AC: 1234 AN: 53284

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.000720 AC: 801 AN: 1111994

Other (OTH) AF: 0.0111 AC: 673 AN: 60390

GnomAD4 genome AF: 0.00885 AC: 1347 AN: 152204 Hom.: 47 Cov.: 32 AF XY: 0.0103 AC XY: 767 AN XY: 74406

African (AFR) AF: 0.00513 AC: 213 AN: 41534

American (AMR) AF: 0.00941 AC: 144 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.116 AC: 602 AN: 5170

South Asian (SAS) AF: 0.00954 AC: 46 AN: 4822

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68010

Other (OTH) AF: 0.0138 AC: 29 AN: 2104

Alfa AF: 0.00212 Hom.: 6

Bravo AF: 0.00911

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.0143 AC: 1741

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.36
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.094	T
Polyphen		0.0	B
Vest4		0.12
MPC		1.6
ClinPred		0.063	T
GERP RS		1.2
PromoterAI		-0.021	Neutral
Varity_R		0.49
gMVP		0.76
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs3734676; hg19: chr6-107780479; COSMIC: COSV64646457;