rs2287074

Variant names:

• chr16-55493201-G-A
• rs2287074
• NM_004530.6:c.1380G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-55493201-G-A
• chr16-55493201-G-C
• chr16-55493201-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004530.6(MMP2):​c.1380G>A​(p.Thr460Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,613,572 control chromosomes in the GnomAD database, including 143,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10744 hom., cov: 31)
  • Exomes 𝑓: 0.42 (133162 hom.)
• Consequence: MMP2 NM_004530.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.24
• Publications: 62 publications found

Genes affected

MMP2 (HGNC:7166): (matrix metallopeptidase 2) This gene is a member of the matrix metalloproteinase (MMP) gene family, that are zinc-dependent enzymes capable of cleaving components of the extracellular matrix and molecules involved in signal transduction. The protein encoded by this gene is a gelatinase A, type IV collagenase, that contains three fibronectin type II repeats in its catalytic site that allow binding of denatured type IV and V collagen and elastin. Unlike most MMP family members, activation of this protein can occur on the cell membrane. This enzyme can be activated extracellularly by proteases, or, intracellulary by its S-glutathiolation with no requirement for proteolytical removal of the pro-domain. This protein is thought to be involved in multiple pathways including roles in the nervous system, endometrial menstrual breakdown, regulation of vascularization, and metastasis. Mutations in this gene have been associated with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis (NAO) syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

MMP2 Gene-Disease associations (from GenCC):

• multicentric osteolysis, nodulosis, and arthropathy

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• multicentric osteolysis-nodulosis-arthropathy spectrum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-55493201-G-A is Benign according to our data. Variant chr16-55493201-G-A is described in ClinVar as Benign. ClinVar VariationId is 319761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.1380G>A	p.Thr460Thr	synonymous_variant	Exon 9 of 13	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.1380G>A	p.Thr460Thr	synonymous_variant	Exon 9 of 13	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55027 AN: 151742 Hom.: 10732 Cov.: 31

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.372

GnomAD2 exomes AF: 0.393 AC: 98853 AN: 251404 AF XY: 0.397

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.424 AC: 619177 AN: 1461712 Hom.: 133162 Cov.: 52 AF XY: 0.423 AC XY: 307693 AN XY: 727164

African (AFR) AF: 0.213 AC: 7137 AN: 33478

American (AMR) AF: 0.412 AC: 18417 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 8338 AN: 26136

East Asian (EAS) AF: 0.318 AC: 12640 AN: 39696

South Asian (SAS) AF: 0.390 AC: 33638 AN: 86252

European-Finnish (FIN) AF: 0.377 AC: 20161 AN: 53418

Middle Eastern (MID) AF: 0.390 AC: 2238 AN: 5740

European-Non Finnish (NFE) AF: 0.443 AC: 492031 AN: 1111884

Other (OTH) AF: 0.407 AC: 24577 AN: 60388

GnomAD4 genome AF: 0.363 AC: 55054 AN: 151860 Hom.: 10744 Cov.: 31 AF XY: 0.360 AC XY: 26720 AN XY: 74236

African (AFR) AF: 0.215 AC: 8920 AN: 41434

American (AMR) AF: 0.418 AC: 6372 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1116 AN: 3472

East Asian (EAS) AF: 0.290 AC: 1486 AN: 5128

South Asian (SAS) AF: 0.380 AC: 1829 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4004 AN: 10544

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29896 AN: 67896

Other (OTH) AF: 0.376 AC: 794 AN: 2112

Alfa AF: 0.420 Hom.: 37564

Bravo AF: 0.359

Asia WGS AF: 0.353 AC: 1227 AN: 3478

EpiCase AF: 0.436

EpiControl AF: 0.438

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multicentric osteolysis nodulosis arthropathy spectrum Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.2
DANN	Benign	0.49
PhyloP100		-3.2
Mutation Taster		=99/1	polymorphism (auto)

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: rs2287074; hg19: chr16-55527113; COSMIC: COSV54599803; COSMIC: COSV54599803;