NM_182943.3:c.2038C>T

Variant names:

• chr3-146071125-G-A
• rs780770356
• NM_182943.3:c.2038C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_182943.3(PLOD2):​c.2038C>T​(p.Arg680*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,458,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PLOD2 NM_182943.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.77
• Publications: 4 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-146071125-G-A is Pathogenic according to our data. Variant chr3-146071125-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2038C>T	p.Arg680*	stop_gained	Exon 19 of 20	NP_891988.1	O00469-2
	PLOD2	NM_000935.3		c.1975C>T	p.Arg659*	stop_gained	Exon 18 of 19	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.2038C>T	p.Arg680*	stop_gained	Exon 19 of 20	ENSP00000282903.5	O00469-2
	PLOD2	ENST00000360060.7	TSL:1	c.1975C>T	p.Arg659*	stop_gained	Exon 18 of 19	ENSP00000353170.3	O00469-1
	PLOD2	ENST00000703518.1		c.2038C>T	p.Arg680*	stop_gained	Exon 21 of 22	ENSP00000515350.1	O00469-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1458924 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 725812

African (AFR) AF: 0.0000300 AC: 1 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1109928

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Bruck syndrome 2 (2)
2	-	-	not provided (2)
1	-	-	Clubfoot;C0345375:Short femur;C0432098:Cleft soft palate;C0685409:Camptodactyly;C1851310:Aplasia/hypoplasia of the femur;C1855340:Bowing of the long bones;C1859399:Radial bowing;C1859461:Femoral bowing;C1865847:Ulnar bowing (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	47
DANN	Uncertain	0.98
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.0045
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		1.8
Vest4		0.88
GERP RS		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780770356; hg19: chr3-145788912; COSMIC: COSV51469342; COSMIC: COSV51469342;