rs9289716

chr3-146106691-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182943.3(PLOD2):c.503-47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 915,488 control chromosomes in the GnomAD database, including 100,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17407 hom., cov: 32)
  • Exomes 𝑓: 0.46 (83132 hom.)
• Consequence: PLOD2 NM_182943.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00700

Genes affected

PLOD2 (HGNC:9082): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) The protein encoded by this gene is a membrane-bound homodimeric enzyme that is localized to the cisternae of the rough endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VIB have deficiencies in lysyl hydroxylase activity. Mutations in the coding region of this gene are associated with Bruck syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-146106691-A-G is Benign according to our data. Variant chr3-146106691-A-G is described in ClinVar as [Benign]. Clinvar id is 674924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD2	NM_182943.3	c.503-47T>C		intron_variant		ENST00000282903.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD2	ENST00000282903.10	c.503-47T>C		intron_variant		1	NM_182943.3	P3

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72401 AN: 151874 Hom.: 17399 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.494

GnomAD3 exomes AF: 0.467 AC: 115638 AN: 247412 Hom.: 27465 AF XY: 0.468 AC XY: 62791 AN XY: 134072

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.592

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.423

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.489

GnomAD4 exome AF: 0.463 AC: 353557 AN: 763494 Hom.: 83132 Cov.: 10 AF XY: 0.464 AC XY: 189121 AN XY: 407384

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.567

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.459

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.486

GnomAD4 genome AF: 0.477 AC: 72442 AN: 151994 Hom.: 17407 Cov.: 32 AF XY: 0.475 AC XY: 35308 AN XY: 74296

Gnomad4 AFR AF: 0.504

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.574

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.488

Alfa AF: 0.482 Hom.: 3912

Bravo AF: 0.481

Asia WGS AF: 0.484 AC: 1684 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bruck syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.0
Dann	Benign	0.73

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

Other links and lift over

dbSNP: rs9289716; hg19: chr3-145824478; COSMIC: COSV51461984; COSMIC: COSV51461984;