rs9289716

Variant names:

• chr3-146106691-A-G
• rs9289716
• NM_182943.3:c.503-47T>C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.00700
• Publications: 8 publications found

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]

PLOD2 Gene-Disease associations (from GenCC):

• Bruck syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Bruck 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 (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 VariationId 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 rank	MANE	Protein	UniProt
PLOD2	NM_182943.3	c.503-47T>C		intron_variant	Intron 4 of 19	ENST00000282903.10	NP_891988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD2	ENST00000282903.10	c.503-47T>C		intron_variant	Intron 4 of 19	1	NM_182943.3	ENSP00000282903.5

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

GnomAD2 exomes AF: 0.467 AC: 115638 AN: 247412 AF XY: 0.468

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 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

African (AFR) AF: 0.509 AC: 10181 AN: 20008

American (AMR) AF: 0.429 AC: 18766 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 12380 AN: 21820

East Asian (EAS) AF: 0.503 AC: 18374 AN: 36514

South Asian (SAS) AF: 0.459 AC: 33172 AN: 72294

European-Finnish (FIN) AF: 0.424 AC: 22033 AN: 51964

Middle Eastern (MID) AF: 0.532 AC: 2354 AN: 4422

European-Non Finnish (NFE) AF: 0.459 AC: 218094 AN: 475246

Other (OTH) AF: 0.486 AC: 18203 AN: 37440

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

African (AFR) AF: 0.504 AC: 20873 AN: 41426

American (AMR) AF: 0.463 AC: 7066 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1993 AN: 3472

East Asian (EAS) AF: 0.563 AC: 2902 AN: 5154

South Asian (SAS) AF: 0.435 AC: 2096 AN: 4820

European-Finnish (FIN) AF: 0.417 AC: 4414 AN: 10578

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31515 AN: 67960

Other (OTH) AF: 0.488 AC: 1026 AN: 2104

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Bruck syndrome 2 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.73
PhyloP100		0.0070
Mutation Taster		=100/0	polymorphism (auto)

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