rs1053605

chr16-55485695-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004530.6(MMP2):c.750C>T(p.Thr250=) 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:4
• Conservation: PhyloP100: -2.00

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP2	NM_004530.6	c.750C>T	p.Thr250=	synonymous_variant	5/13	ENST00000219070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP2	ENST00000219070.9	c.750C>T	p.Thr250=	synonymous_variant	5/13	1	NM_004530.6	P1

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

GnomAD3 exomes AF: 0.0726 AC: 18249 AN: 251482 Hom.: 813 AF XY: 0.0759 AC XY: 10319 AN XY: 135914

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 SAS exome AF: 0.121

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

Gnomad4 AFR exome AF: 0.0491

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.0598

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.0504

Gnomad4 NFE exome AF: 0.0702

Gnomad4 OTH exome AF: 0.0780

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

Gnomad4 AFR AF: 0.0451

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0525

Gnomad4 NFE AF: 0.0698

Gnomad4 OTH AF: 0.0734

Alfa AF: 0.0698 Hom.: 670

Bravo AF: 0.0619

Asia WGS AF: 0.168 AC: 582 AN: 3478

EpiCase AF: 0.0704

EpiControl AF: 0.0742

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multicentric osteolysis nodulosis arthropathy spectrum Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0050
Dann	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs1053605; hg19: chr16-55519607; COSMIC: COSV54599793; COSMIC: COSV54599793;