rs243865

Variant names:

• chr16-55477894-C-T
• rs243865
• ENST00000570308.5:c.-75-5015C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000570308.5(MMP2):c.-75-5015C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000570308.5 is not a MANE Select or MANE Plus Clinical transcript for MMP2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.187 (AC=28,505) in the gnomAD database across 152,156 control chromosomes, including 3,255 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.246. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency: Genomes: 𝑓 0.19 (3255 hom., cov: 32)
• Consequence: MMP2 ENST00000570308.5 intron
• Clinical Significance: association criteria provided, single submitter O:1
• Conservation: PhyloP100: -1.93
• Publications: 462 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, PanelApp Australia
• multicentric osteolysis-nodulosis-arthropathy spectrum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2457 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000570308.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000570308.5	TSL:1	c.-75-5015C>T		intron	N/A	ENSP00000461421.1	P08253-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.187	AC:28505	Hom:3258	AN:152036	Cov:32
GnomAD4 genome	AF: 0.187	AC:28505	Hom:3255	AN:152156	Cov:32
TOPMed (Bravo)	AF: 0.174	AC:46136	Hom:4924	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.210	AC:60498	Hom:7072	AN:288052	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.184	AC:431	Hom:46	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.110	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.207	AC:62	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.123	AC:426	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0840	AC:607	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.142	AC:25	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0714	AC:8762	Hom:333	AN:122780	Cov:
Turkish Variome	AF: 0.212	AC:328	Hom:33	AN:1546	Cov:
UK10K	AF: 0.261	AC:1970	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.108	AC:970	Hom:57	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: association

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	-	Lip and oral cavity carcinoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.7
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.30
DANN	Benign	0.84
GPN-Star LLR	N/A	0.20
GPN-Star score	N/A	-0.20
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.9

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs243865;

hg19: chr16-55511806;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar