rs243834

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004530.6(MMP2):c.1770-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,611,146 control chromosomes in the GnomAD database, including 185,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15862 hom., cov: 32)

Exomes 𝑓: 0.48 ( 169406 hom. )

Consequence

MMP2
NM_004530.6 splice_region, intron

Scores

Splicing: ADA: 0.00007448

Clinical Significance

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

Conservation

PhyloP100: -0.0560

Publications

33 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 16-55502775-A-G is Benign according to our data. Variant chr16-55502775-A-G is described in ClinVar as Benign. ClinVar VariationId is 319766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 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	Effect	Exon Rank	Protein
MMP2	NM_004530.6	MANE Select	c.1770-4A>G	splice_region intron	N/A	NP_004521.1
MMP2	NM_001127891.3		c.1620-4A>G	splice_region intron	N/A	NP_001121363.1
MMP2	NM_001302508.1		c.1542-4A>G	splice_region intron	N/A	NP_001289437.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MMP2	ENST00000219070.9	TSL:1 MANE Select	c.1770-4A>G	splice_region intron	N/A	ENSP00000219070.4
MMP2	ENST00000437642.6	TSL:1	c.1620-4A>G	splice_region intron	N/A	ENSP00000394237.2
MMP2	ENST00000570308.5	TSL:1	c.1542-4A>G	splice_region intron	N/A	ENSP00000461421.1

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

68923

AN:

151824

Hom.:

15857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.384

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.437

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.530

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.450

GnomAD2 exomes

AF:

0.487

AC:

122368

AN:

251062

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.379

Gnomad AMR exome

AF:

0.481

Gnomad ASJ exome

AF:

0.446

Gnomad EAS exome

AF:

0.635

Gnomad FIN exome

AF:

0.525

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.473

GnomAD4 exome

AF:

0.480

AC:

700877

AN:

1459206

Hom.:

169406

Cov.:

AF XY:

0.481

AC XY:

349122

AN XY:

726050

show subpopulations

African (AFR)

AF:

0.380

AC:

12711

AN:

33446

American (AMR)

AF:

0.479

AC:

21405

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

11737

AN:

26120

East Asian (EAS)

AF:

0.629

AC:

24967

AN:

39684

South Asian (SAS)

AF:

0.517

AC:

44549

AN:

86222

European-Finnish (FIN)

AF:

0.516

AC:

27502

AN:

53326

Middle Eastern (MID)

AF:

0.421

AC:

2411

AN:

5730

European-Non Finnish (NFE)

AF:

0.475

AC:

527026

AN:

1109684

Other (OTH)

AF:

0.474

AC:

28569

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

18908

37816

56725

75633

94541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15764

31528

47292

63056

78820

<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:

0.454

AC:

68947

AN:

151940

Hom.:

15862

Cov.:

AF XY:

0.458

AC XY:

33978

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.384

AC:

15908

AN:

41424

American (AMR)

AF:

0.451

AC:

6887

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

1515

AN:

3466

East Asian (EAS)

AF:

0.641

AC:

3295

AN:

5140

South Asian (SAS)

AF:

0.530

AC:

2556

AN:

4820

European-Finnish (FIN)

AF:

0.520

AC:

5492

AN:

10562

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.470

AC:

31912

AN:

67942

Other (OTH)

AF:

0.447

AC:

945

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1932

3863

5795

7726

9658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<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:

0.462

Hom.:

32961

Bravo

AF:

0.446

Asia WGS

AF:

0.550

AC:

1916

AN:

3478

EpiCase

AF:

0.469

EpiControl

AF:

0.469

ClinVar

ClinVar submissions as Germline

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

-0.72

CADD

Benign

8.2

(source)

DANN

Benign

0.71

PhyloP100

-0.056

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000074

dbscSNV1_RF

Benign

0.0080

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

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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