rs4681297

Variant names:

• chr3-146121108-C-T
• rs4681297
• NM_182943.3:c.338+4G>A

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.338+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,585,818 control chromosomes in the GnomAD database, including 467,888 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46019 hom., cov: 31)
  • Exomes 𝑓: 0.77 (421869 hom.)
• Consequence: PLOD2 NM_182943.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004899
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.509
• Publications: 13 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-146121108-C-T is Benign according to our data. Variant chr3-146121108-C-T is described in ClinVar as Benign. ClinVar VariationId is 263074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 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.338+4G>A		splice_region intron	N/A	NP_891988.1	O00469-2
	PLOD2	NM_000935.3		c.338+4G>A		splice_region 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.338+4G>A		splice_region intron	N/A	ENSP00000282903.5	O00469-2
	PLOD2	ENST00000360060.7	TSL:1	c.338+4G>A		splice_region intron	N/A	ENSP00000353170.3	O00469-1
	PLOD2	ENST00000703518.1		c.338+4G>A		splice_region intron	N/A	ENSP00000515350.1	O00469-2

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118090 AN: 151902 Hom.: 45978 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.782

GnomAD2 exomes AF: 0.765 AC: 191652 AN: 250686 AF XY: 0.763

Gnomad AFR exome AF: 0.813

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.842

Gnomad EAS exome AF: 0.846

Gnomad FIN exome AF: 0.710

Gnomad NFE exome AF: 0.769

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.766 AC: 1098486 AN: 1433798 Hom.: 421869 Cov.: 28 AF XY: 0.765 AC XY: 547281 AN XY: 715498

African (AFR) AF: 0.819 AC: 26966 AN: 32910

American (AMR) AF: 0.728 AC: 32490 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 21994 AN: 25970

East Asian (EAS) AF: 0.805 AC: 31802 AN: 39530

South Asian (SAS) AF: 0.731 AC: 62651 AN: 85704

European-Finnish (FIN) AF: 0.704 AC: 37434 AN: 53154

Middle Eastern (MID) AF: 0.800 AC: 4580 AN: 5728

European-Non Finnish (NFE) AF: 0.768 AC: 834323 AN: 1086692

Other (OTH) AF: 0.778 AC: 46246 AN: 59474

GnomAD4 genome AF: 0.777 AC: 118189 AN: 152020 Hom.: 46019 Cov.: 31 AF XY: 0.773 AC XY: 57413 AN XY: 74270

African (AFR) AF: 0.815 AC: 33816 AN: 41482

American (AMR) AF: 0.743 AC: 11337 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2915 AN: 3472

East Asian (EAS) AF: 0.833 AC: 4305 AN: 5170

South Asian (SAS) AF: 0.728 AC: 3493 AN: 4796

European-Finnish (FIN) AF: 0.707 AC: 7458 AN: 10550

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.769 AC: 52308 AN: 67980

Other (OTH) AF: 0.785 AC: 1658 AN: 2112

Alfa AF: 0.777 Hom.: 200623

Bravo AF: 0.783

Asia WGS AF: 0.801 AC: 2786 AN: 3478

EpiCase AF: 0.776

EpiControl AF: 0.774

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Bruck syndrome 2 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	17
DANN	Benign	0.38
PhyloP100		0.51
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.018
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: rs4681297; hg19: chr3-145838895;