NM_004530.6:c.833-255G>C

Variant names:

• chr16-55488288-G-C
• rs2241145
• NM_004530.6:c.833-255G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004530.6(MMP2):​c.833-255G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 528,814 control chromosomes in the GnomAD database, including 56,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16436 hom., cov: 33)
  • Exomes 𝑓: 0.46 (40341 hom.)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.94
• Publications: 27 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

ENSG00000279030 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-55488288-G-C is Benign according to our data. Variant chr16-55488288-G-C is described in ClinVar as Benign. ClinVar VariationId is 1280447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 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.833-255G>C		intron	N/A	NP_004521.1
	MMP2	NM_001127891.3		c.683-255G>C		intron	N/A	NP_001121363.1
	MMP2	NM_001302508.1		c.605-255G>C		intron	N/A	NP_001289437.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000219070.9	TSL:1 MANE Select	c.833-255G>C		intron	N/A	ENSP00000219070.4
	MMP2	ENST00000437642.6	TSL:1	c.683-255G>C		intron	N/A	ENSP00000394237.2
	MMP2	ENST00000570308.5	TSL:1	c.605-255G>C		intron	N/A	ENSP00000461421.1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70683 AN: 151994 Hom.: 16403 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.472

GnomAD4 exome AF: 0.459 AC: 173033 AN: 376702 Hom.: 40341 Cov.: 3 AF XY: 0.462 AC XY: 92019 AN XY: 199336

African (AFR) AF: 0.477 AC: 5210 AN: 10920

American (AMR) AF: 0.514 AC: 8647 AN: 16820

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 4555 AN: 11464

East Asian (EAS) AF: 0.501 AC: 12085 AN: 24128

South Asian (SAS) AF: 0.512 AC: 22956 AN: 44818

European-Finnish (FIN) AF: 0.420 AC: 9131 AN: 21752

Middle Eastern (MID) AF: 0.467 AC: 762 AN: 1630

European-Non Finnish (NFE) AF: 0.447 AC: 99874 AN: 223512

Other (OTH) AF: 0.453 AC: 9813 AN: 21658

GnomAD4 genome AF: 0.465 AC: 70756 AN: 152112 Hom.: 16436 Cov.: 33 AF XY: 0.466 AC XY: 34643 AN XY: 74352

African (AFR) AF: 0.481 AC: 19975 AN: 41494

American (AMR) AF: 0.504 AC: 7710 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1425 AN: 3468

East Asian (EAS) AF: 0.489 AC: 2528 AN: 5170

South Asian (SAS) AF: 0.507 AC: 2441 AN: 4810

European-Finnish (FIN) AF: 0.418 AC: 4421 AN: 10584

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30602 AN: 67978

Other (OTH) AF: 0.476 AC: 1004 AN: 2110

Alfa AF: 0.459 Hom.: 2047

Bravo AF: 0.472

Asia WGS AF: 0.521 AC: 1814 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.055
DANN	Benign	0.47
PhyloP100		-1.9
PromoterAI		-0.019	Neutral
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: rs2241145; hg19: chr16-55522200; COSMIC: COSV54602148; COSMIC: COSV54602148;