rs4681294

Variant names:

• chr3-146077353-G-A
• rs4681294
• NM_182943.3:c.1564-458C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182943.3(PLOD2):​c.1564-458C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 179,440 control chromosomes in the GnomAD database, including 19,439 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16437 hom., cov: 32)
  • Exomes 𝑓: 0.46 (3002 hom.)
• Consequence: PLOD2 NM_182943.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P
• Bruck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000243415 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182943.3. 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
	PLOD2	NM_182943.3	MANE Select	c.1564-458C>T		intron	N/A	NP_891988.1	O00469-2
	PLOD2	NM_000935.3		c.1501-458C>T		intron	N/A	NP_000926.2	O00469-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD2	ENST00000282903.10	TSL:1 MANE Select	c.1564-458C>T		intron	N/A	ENSP00000282903.5	O00469-2
	PLOD2	ENST00000360060.7	TSL:1	c.1501-458C>T		intron	N/A	ENSP00000353170.3	O00469-1
	PLOD2	ENST00000478436.1	TSL:1	n.2407C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70275 AN: 151280 Hom.: 16431 Cov.: 32

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.480

GnomAD4 exome AF: 0.458 AC: 12852 AN: 28042 Hom.: 3002 Cov.: 4 AF XY: 0.463 AC XY: 6682 AN XY: 14428

African (AFR) AF: 0.505 AC: 214 AN: 424

American (AMR) AF: 0.455 AC: 378 AN: 830

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 159 AN: 262

East Asian (EAS) AF: 0.565 AC: 216 AN: 382

South Asian (SAS) AF: 0.498 AC: 643 AN: 1290

European-Finnish (FIN) AF: 0.426 AC: 144 AN: 338

Middle Eastern (MID) AF: 0.650 AC: 39 AN: 60

European-Non Finnish (NFE) AF: 0.450 AC: 10547 AN: 23424

Other (OTH) AF: 0.496 AC: 512 AN: 1032

GnomAD4 genome AF: 0.464 AC: 70315 AN: 151398 Hom.: 16437 Cov.: 32 AF XY: 0.464 AC XY: 34336 AN XY: 73998

African (AFR) AF: 0.500 AC: 20695 AN: 41356

American (AMR) AF: 0.448 AC: 6777 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1951 AN: 3456

East Asian (EAS) AF: 0.564 AC: 2900 AN: 5144

South Asian (SAS) AF: 0.434 AC: 2096 AN: 4826

European-Finnish (FIN) AF: 0.408 AC: 4295 AN: 10528

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30057 AN: 67642

Other (OTH) AF: 0.474 AC: 997 AN: 2102

Alfa AF: 0.455 Hom.: 2671

Bravo AF: 0.468

Asia WGS AF: 0.482 AC: 1678 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.26
DANN	Benign	0.42
PhyloP100		-0.25
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: rs4681294; hg19: chr3-145795140;