dbSNP rs2287074: MMP2:p.Thr460Thr (chr16-55493201-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004530.6(MMP2):c.1380G>A(p.Thr460Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,613,572 control chromosomes in the GnomAD database, including 143,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10744 hom., cov: 31)

Exomes 𝑓: 0.42 ( 133162 hom. )

Consequence

MMP2
NM_004530.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.24

Publications

62 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
multicentric osteolysis-nodulosis-arthropathy spectrum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 16-55493201-G-A is Benign according to our data. Variant chr16-55493201-G-A is described in ClinVar as Benign. ClinVar VariationId is 319761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004530.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP2	NM_004530.6	MANE Select	c.1380G>A	p.Thr460Thr	synonymous	Exon 9 of 13	NP_004521.1	P08253-1
MMP2	NM_001127891.3		c.1230G>A	p.Thr410Thr	synonymous	Exon 9 of 13	NP_001121363.1	P08253-3
MMP2	NM_001302508.1		c.1152G>A	p.Thr384Thr	synonymous	Exon 9 of 13	NP_001289437.1	P08253-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMP2	ENST00000219070.9	TSL:1 MANE Select	c.1380G>A	p.Thr460Thr	synonymous	Exon 9 of 13	ENSP00000219070.4	P08253-1
MMP2	ENST00000437642.6	TSL:1	c.1230G>A	p.Thr410Thr	synonymous	Exon 9 of 13	ENSP00000394237.2	P08253-3
MMP2	ENST00000570308.5	TSL:1	c.1152G>A	p.Thr384Thr	synonymous	Exon 10 of 14	ENSP00000461421.1	P08253-2

Frequencies

GnomAD3 genomes

AF:

0.363

AC:

55027

AN:

151742

Hom.:

10732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.576

Gnomad AMR

AF:

0.418

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.290

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.380

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.440

Gnomad OTH

AF:

0.372

GnomAD2 exomes

AF:

0.393

AC:

98853

AN:

251404

AF XY:

0.397

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.373

Gnomad NFE exome

AF:

0.440

Gnomad OTH exome

AF:

0.398

GnomAD4 exome

AF:

0.424

AC:

619177

AN:

1461712

Hom.:

133162

Cov.:

AF XY:

0.423

AC XY:

307693

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.213

AC:

7137

AN:

33478

American (AMR)

AF:

0.412

AC:

18417

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

8338

AN:

26136

East Asian (EAS)

AF:

0.318

AC:

12640

AN:

39696

South Asian (SAS)

AF:

0.390

AC:

33638

AN:

86252

European-Finnish (FIN)

AF:

0.377

AC:

20161

AN:

53418

Middle Eastern (MID)

AF:

0.390

AC:

2238

AN:

5740

European-Non Finnish (NFE)

AF:

0.443

AC:

492031

AN:

1111884

Other (OTH)

AF:

0.407

AC:

24577

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

20487

40974

61462

81949

102436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14682

29364

44046

58728

73410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.363

AC:

55054

AN:

151860

Hom.:

10744

Cov.:

AF XY:

0.360

AC XY:

26720

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.215

AC:

8920

AN:

41434

American (AMR)

AF:

0.418

AC:

6372

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1116

AN:

3472

East Asian (EAS)

AF:

0.290

AC:

1486

AN:

5128

South Asian (SAS)

AF:

0.380

AC:

1829

AN:

4816

European-Finnish (FIN)

AF:

0.380

AC:

4004

AN:

10544

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.440

AC:

29896

AN:

67896

Other (OTH)

AF:

0.376

AC:

794

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1764

3528

5293

7057

8821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.420

Hom.:

37564

Bravo

AF:

0.359

Asia WGS

AF:

0.353

AC:

1227

AN:

3478

EpiCase

AF:

0.436

EpiControl

AF:

0.438

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Multicentric osteolysis nodulosis arthropathy spectrum (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.2

(source)

DANN

Benign

0.49

PhyloP100

-3.2

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over