rs1053605

Variant names:

• chr16-55485695-C-T
• rs1053605
• NM_004530.6:c.750C>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.750C>T​(p.Thr250Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0722 in 1,614,064 control chromosomes in the GnomAD database, including 4,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (356 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4355 hom.)
• Consequence: MMP2 NM_004530.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.00
• Publications: 46 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.85).
• BP6: Variant 16-55485695-C-T is Benign according to our data. Variant chr16-55485695-C-T is described in ClinVar as Benign. ClinVar VariationId is 319751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004530.6. 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
	MMP2	NM_004530.6	MANE Select	c.750C>T	p.Thr250Thr	synonymous	Exon 5 of 13	NP_004521.1	P08253-1
	MMP2	NM_001127891.3		c.600C>T	p.Thr200Thr	synonymous	Exon 5 of 13	NP_001121363.1	P08253-3
	MMP2	NM_001302508.1		c.522C>T	p.Thr174Thr	synonymous	Exon 5 of 13	NP_001289437.1	P08253-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000219070.9	TSL:1 MANE Select	c.750C>T	p.Thr250Thr	synonymous	Exon 5 of 13	ENSP00000219070.4	P08253-1
	MMP2	ENST00000437642.6	TSL:1	c.600C>T	p.Thr200Thr	synonymous	Exon 5 of 13	ENSP00000394237.2	P08253-3
	MMP2	ENST00000570308.5	TSL:1	c.522C>T	p.Thr174Thr	synonymous	Exon 6 of 14	ENSP00000461421.1	P08253-2

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9661 AN: 152090 Hom.: 349 Cov.: 32

Gnomad AFR AF: 0.0452

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0698

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0726 AC: 18249 AN: 251482 AF XY: 0.0759

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.0324

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0679

Gnomad OTH exome AF: 0.0663

GnomAD4 exome AF: 0.0731 AC: 106793 AN: 1461856 Hom.: 4355 Cov.: 35 AF XY: 0.0747 AC XY: 54312 AN XY: 727222

African (AFR) AF: 0.0491 AC: 1644 AN: 33476

American (AMR) AF: 0.0354 AC: 1585 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0598 AC: 1564 AN: 26134

East Asian (EAS) AF: 0.147 AC: 5827 AN: 39700

South Asian (SAS) AF: 0.120 AC: 10332 AN: 86258

European-Finnish (FIN) AF: 0.0504 AC: 2690 AN: 53420

Middle Eastern (MID) AF: 0.0638 AC: 368 AN: 5768

European-Non Finnish (NFE) AF: 0.0702 AC: 78070 AN: 1111984

Other (OTH) AF: 0.0780 AC: 4713 AN: 60392

GnomAD4 genome AF: 0.0636 AC: 9679 AN: 152208 Hom.: 356 Cov.: 32 AF XY: 0.0642 AC XY: 4775 AN XY: 74418

African (AFR) AF: 0.0451 AC: 1873 AN: 41526

American (AMR) AF: 0.0453 AC: 693 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3472

East Asian (EAS) AF: 0.146 AC: 754 AN: 5164

South Asian (SAS) AF: 0.128 AC: 615 AN: 4818

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0698 AC: 4745 AN: 67996

Other (OTH) AF: 0.0734 AC: 155 AN: 2112

Alfa AF: 0.0689 Hom.: 792

Bravo AF: 0.0619

Asia WGS AF: 0.168 AC: 582 AN: 3478

EpiCase AF: 0.0704

EpiControl AF: 0.0742

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Multicentric osteolysis nodulosis arthropathy spectrum (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.55
PhyloP100		-2.0
Mutation Taster		=98/2	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: rs1053605; hg19: chr16-55519607; COSMIC: COSV54599793; COSMIC: COSV54599793;