rs243834

Variant names:

• chr16-55502775-A-G
• rs243834
• NM_004530.6:c.1770-4A>G

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.1770-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,611,146 control chromosomes in the GnomAD database, including 185,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15862 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169406 hom.)
• Consequence: MMP2 NM_004530.6 splice_region, intron
• Scores: Splicing: ADA: 0.00007448
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0560
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-55502775-A-G is Benign according to our data. Variant chr16-55502775-A-G is described in ClinVar as Benign. ClinVar VariationId is 319766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.1770-4A>G		splice_region_variant, intron_variant	Intron 11 of 12	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.1770-4A>G		splice_region_variant, intron_variant	Intron 11 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68923 AN: 151824 Hom.: 15857 Cov.: 32

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.487 AC: 122368 AN: 251062 AF XY: 0.489

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.480 AC: 700877 AN: 1459206 Hom.: 169406 Cov.: 31 AF XY: 0.481 AC XY: 349122 AN XY: 726050

African (AFR) AF: 0.380 AC: 12711 AN: 33446

American (AMR) AF: 0.479 AC: 21405 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 11737 AN: 26120

East Asian (EAS) AF: 0.629 AC: 24967 AN: 39684

South Asian (SAS) AF: 0.517 AC: 44549 AN: 86222

European-Finnish (FIN) AF: 0.516 AC: 27502 AN: 53326

Middle Eastern (MID) AF: 0.421 AC: 2411 AN: 5730

European-Non Finnish (NFE) AF: 0.475 AC: 527026 AN: 1109684

Other (OTH) AF: 0.474 AC: 28569 AN: 60288

GnomAD4 genome AF: 0.454 AC: 68947 AN: 151940 Hom.: 15862 Cov.: 32 AF XY: 0.458 AC XY: 33978 AN XY: 74266

African (AFR) AF: 0.384 AC: 15908 AN: 41424

American (AMR) AF: 0.451 AC: 6887 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1515 AN: 3466

East Asian (EAS) AF: 0.641 AC: 3295 AN: 5140

South Asian (SAS) AF: 0.530 AC: 2556 AN: 4820

European-Finnish (FIN) AF: 0.520 AC: 5492 AN: 10562

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31912 AN: 67942

Other (OTH) AF: 0.447 AC: 945 AN: 2112

Alfa AF: 0.462 Hom.: 32961

Bravo AF: 0.446

Asia WGS AF: 0.550 AC: 1916 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.469

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.72
CADD	Benign	8.2
DANN	Benign	0.71
PhyloP100		-0.056
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.0080
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: rs243834; hg19: chr16-55536687; COSMIC: COSV54599748; COSMIC: COSV54599748;