chr16-55498546-T-C

Variant names:

• chr16-55498546-T-C
• rs2287076
• NM_004530.6:c.1769+98T>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.1769+98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,539,242 control chromosomes in the GnomAD database, including 137,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10460 hom., cov: 33)
  • Exomes 𝑓: 0.42 (126847 hom.)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05
• Publications: 16 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=-0.89).
• BP6: Variant 16-55498546-T-C is Benign according to our data. Variant chr16-55498546-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1769+98T>C		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.1769+98T>C		intron_variant	Intron 11 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53831 AN: 152028 Hom.: 10449 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.425 AC: 589452 AN: 1387096 Hom.: 126847 AF XY: 0.424 AC XY: 294248 AN XY: 693538

African (AFR) AF: 0.180 AC: 5733 AN: 31920

American (AMR) AF: 0.412 AC: 18149 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8222 AN: 25642

East Asian (EAS) AF: 0.331 AC: 12989 AN: 39294

South Asian (SAS) AF: 0.392 AC: 32893 AN: 83914

European-Finnish (FIN) AF: 0.381 AC: 19108 AN: 50148

Middle Eastern (MID) AF: 0.392 AC: 2096 AN: 5346

European-Non Finnish (NFE) AF: 0.445 AC: 466689 AN: 1048958

Other (OTH) AF: 0.407 AC: 23573 AN: 57864

GnomAD4 genome AF: 0.354 AC: 53854 AN: 152146 Hom.: 10460 Cov.: 33 AF XY: 0.352 AC XY: 26185 AN XY: 74362

African (AFR) AF: 0.183 AC: 7581 AN: 41524

American (AMR) AF: 0.419 AC: 6403 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1124 AN: 3470

East Asian (EAS) AF: 0.304 AC: 1568 AN: 5158

South Asian (SAS) AF: 0.382 AC: 1843 AN: 4824

European-Finnish (FIN) AF: 0.380 AC: 4022 AN: 10586

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29908 AN: 67978

Other (OTH) AF: 0.365 AC: 772 AN: 2116

Alfa AF: 0.419 Hom.: 16153

Bravo AF: 0.349

Asia WGS AF: 0.357 AC: 1242 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	-0.89
CADD	Benign	0.059
DANN	Benign	0.40
PhyloP100		-1.1
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: rs2287076; hg19: chr16-55532458; COSMIC: COSV107264297;