rs7201

Positions:

• chr16-55505702-A-C
• chr16-55505702-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004530.6(MMP2):​c.*260A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 543,508 control chromosomes in the GnomAD database, including 45,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11221 hom., cov: 32)
  • Exomes 𝑓: 0.41 (34745 hom.)
• Consequence: MMP2 NM_004530.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.245

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-55505702-A-C is Benign according to our data. Variant chr16-55505702-A-C is described in ClinVar as [Benign]. Clinvar id is 319776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP2	NM_004530.6	c.*260A>C		3_prime_UTR_variant	13/13	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.*260A>C		3_prime_UTR_variant	13/13	1	NM_004530.6	ENSP00000219070	P1
MMP2	ENST00000437642.6	c.*260A>C		3_prime_UTR_variant	13/13	1		ENSP00000394237
MMP2	ENST00000570308.5	c.*260A>C		3_prime_UTR_variant	14/14	1		ENSP00000461421
MMP2	ENST00000566564.1	c.*137+123A>C		intron_variant, NMD_transcript_variant		3		ENSP00000461915

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55890 AN: 151826 Hom.: 11216 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.413 AC: 161820 AN: 391564 Hom.: 34745 Cov.: 1 AF XY: 0.409 AC XY: 84517 AN XY: 206612

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.394

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.368 AC: 55911 AN: 151944 Hom.: 11221 Cov.: 32 AF XY: 0.364 AC XY: 27063 AN XY: 74258

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.391

Alfa AF: 0.437 Hom.: 24938

Bravo AF: 0.365

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 23364396) -

Multicentric osteolysis nodulosis arthropathy spectrum Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.0
DANN	Benign	0.71

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: rs7201; hg19: chr16-55539614; COSMIC: COSV50900244; COSMIC: COSV50900244;