rs1030868

Variant names:

• chr16-55482855-G-A
• rs1030868
• NM_004530.6:c.154-54G>A

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.154-54G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,486,456 control chromosomes in the GnomAD database, including 97,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10572 hom., cov: 32)
  • Exomes 𝑓: 0.36 (86528 hom.)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.72
• Publications: 17 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=-0.94).
• BP6: Variant 16-55482855-G-A is Benign according to our data. Variant chr16-55482855-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.154-54G>A		intron_variant	Intron 1 of 12	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.154-54G>A		intron_variant	Intron 1 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56640 AN: 151906 Hom.: 10547 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.358 AC: 477971 AN: 1334432 Hom.: 86528 AF XY: 0.356 AC XY: 238503 AN XY: 670230

African (AFR) AF: 0.414 AC: 12825 AN: 30986

American (AMR) AF: 0.444 AC: 19326 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 7807 AN: 25196

East Asian (EAS) AF: 0.280 AC: 10903 AN: 38926

South Asian (SAS) AF: 0.314 AC: 26120 AN: 83188

European-Finnish (FIN) AF: 0.319 AC: 16683 AN: 52368

Middle Eastern (MID) AF: 0.348 AC: 1915 AN: 5502

European-Non Finnish (NFE) AF: 0.363 AC: 362783 AN: 998608

Other (OTH) AF: 0.350 AC: 19609 AN: 56102

GnomAD4 genome AF: 0.373 AC: 56699 AN: 152024 Hom.: 10572 Cov.: 32 AF XY: 0.370 AC XY: 27485 AN XY: 74304

African (AFR) AF: 0.412 AC: 17060 AN: 41446

American (AMR) AF: 0.424 AC: 6483 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1080 AN: 3470

East Asian (EAS) AF: 0.250 AC: 1289 AN: 5156

South Asian (SAS) AF: 0.298 AC: 1439 AN: 4824

European-Finnish (FIN) AF: 0.316 AC: 3340 AN: 10562

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24678 AN: 67976

Other (OTH) AF: 0.366 AC: 772 AN: 2110

Alfa AF: 0.378 Hom.: 1339

Bravo AF: 0.384

Asia WGS AF: 0.266 AC: 924 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.031
DANN	Benign	0.15
PhyloP100		-2.7
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: rs1030868; hg19: chr16-55516767; COSMIC: COSV54603548; COSMIC: COSV54603548;