3-146117596-A-G

Variant names:

• chr3-146117596-A-G
• rs12496198
• NM_182943.3:c.338+3516T>C

Variant summary

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

The NM_182943.3(PLOD2):​c.338+3516T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 151,834 control chromosomes in the GnomAD database, including 15,076 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 0.44 (15076 hom., cov: 31)
• Consequence: PLOD2 NM_182943.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• 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.338+3516T>C		intron	N/A	NP_891988.1	O00469-2
	PLOD2	NM_000935.3		c.338+3516T>C		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+3516T>C		intron	N/A	ENSP00000282903.5	O00469-2
	PLOD2	ENST00000360060.7	TSL:1	c.338+3516T>C		intron	N/A	ENSP00000353170.3	O00469-1
	PLOD2	ENST00000703518.1		c.338+3516T>C		intron	N/A	ENSP00000515350.1	O00469-2

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67348 AN: 151714 Hom.: 15076 Cov.: 31

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.468

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.444 AC: 67373 AN: 151834 Hom.: 15076 Cov.: 31 AF XY: 0.442 AC XY: 32807 AN XY: 74192

African (AFR) AF: 0.421 AC: 17440 AN: 41400

American (AMR) AF: 0.451 AC: 6882 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1966 AN: 3466

East Asian (EAS) AF: 0.564 AC: 2901 AN: 5144

South Asian (SAS) AF: 0.431 AC: 2068 AN: 4794

European-Finnish (FIN) AF: 0.376 AC: 3974 AN: 10560

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.451 AC: 30636 AN: 67912

Other (OTH) AF: 0.463 AC: 977 AN: 2112

Alfa AF: 0.448 Hom.: 5430

Bravo AF: 0.448

Asia WGS AF: 0.475 AC: 1652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.19
DANN	Benign	0.38
PhyloP100		-2.3
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: rs12496198; hg19: chr3-145835383;