3-146092816-T-G

Variant names:

• chr3-146092816-T-G
• rs3804663
• NM_182943.3:c.778-915A>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.778-915A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,046 control chromosomes in the GnomAD database, including 2,926 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 0.18 (2926 hom., cov: 32)
• Consequence: PLOD2 NM_182943.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 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.778-915A>C		intron	N/A	NP_891988.1	O00469-2
	PLOD2	NM_000935.3		c.778-915A>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.778-915A>C		intron	N/A	ENSP00000282903.5	O00469-2
	PLOD2	ENST00000360060.7	TSL:1	c.778-915A>C		intron	N/A	ENSP00000353170.3	O00469-1
	PLOD2	ENST00000703518.1		c.778-915A>C		intron	N/A	ENSP00000515350.1	O00469-2

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27232 AN: 151928 Hom.: 2925 Cov.: 32

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.179 AC: 27235 AN: 152046 Hom.: 2926 Cov.: 32 AF XY: 0.185 AC XY: 13730 AN XY: 74344

African (AFR) AF: 0.0525 AC: 2181 AN: 41550

American (AMR) AF: 0.236 AC: 3614 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3462

East Asian (EAS) AF: 0.156 AC: 809 AN: 5172

South Asian (SAS) AF: 0.260 AC: 1256 AN: 4824

European-Finnish (FIN) AF: 0.290 AC: 3066 AN: 10560

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15151 AN: 67882

Other (OTH) AF: 0.186 AC: 392 AN: 2110

Alfa AF: 0.112 Hom.: 225

Bravo AF: 0.168

Asia WGS AF: 0.169 AC: 589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.49
PhyloP100		-0.085
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: rs3804663; hg19: chr3-145810603;