6-107459275-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020381.4(PDSS2):​c.11G>A​(p.Arg4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDSS2 NM_020381.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10842115).

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>A	p.Arg4Gln	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>A	p.Arg4Gln	missense	Exon 1 of 8	ENSP00000358033.4
	PDSS2	ENST00000369031.4	TSL:1	c.11G>A	p.Arg4Gln	missense	Exon 1 of 4	ENSP00000358027.4
	PDSS2	ENST00000900080.1		c.11G>A	p.Arg4Gln	missense	Exon 1 of 9	ENSP00000570139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 6

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.36
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.31		Loss of MoRF binding (P = 0.0026)
MVP		0.53
MPC		1.3
ClinPred		0.77	D
GERP RS		1.2
PromoterAI		-0.087	Neutral
Varity_R		0.13
gMVP		0.62
Mutation Taster		=95/5	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: rs3734676; hg19: chr6-107780479;