rs1417381110

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004530.6(MMP2):​c.41T>C​(p.Leu14Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,605,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MMP2
NM_004530.6 missense

Scores

3
5
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MMP2NM_004530.6 linkc.41T>C p.Leu14Pro missense_variant Exon 1 of 13 ENST00000219070.9 NP_004521.1 P08253-1A0A024R6R4
MMP2NM_001302508.1 linkc.-76+555T>C intron_variant Intron 1 of 12 NP_001289437.1 P08253-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMP2ENST00000219070.9 linkc.41T>C p.Leu14Pro missense_variant Exon 1 of 13 1 NM_004530.6 ENSP00000219070.4 P08253-1
MMP2ENST00000570308.5 linkc.-75-3389T>C intron_variant Intron 2 of 13 1 ENSP00000461421.1 P08253-2
MMP2ENST00000568715.5 linkc.-76+555T>C intron_variant Intron 1 of 3 4 ENSP00000457949.1 H3BV48

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
226698
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000688
AC:
10
AN:
1452922
Hom.:
0
Cov.:
31
AF XY:
0.00000692
AC XY:
5
AN XY:
722198
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33306
American (AMR)
AF:
0.00
AC:
0
AN:
43788
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25924
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39336
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85194
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51252
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5706
European-Non Finnish (NFE)
AF:
0.00000902
AC:
10
AN:
1108500
Other (OTH)
AF:
0.00
AC:
0
AN:
59916
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41422
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5152
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 19, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.41T>C (p.L14P) alteration is located in exon 1 (coding exon 1) of the MMP2 gene. This alteration results from a T to C substitution at nucleotide position 41, causing the leucine (L) at amino acid position 14 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.041
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T
Eigen
Benign
0.11
Eigen_PC
Benign
0.066
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.53
T
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
M
PhyloP100
3.7
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.27
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.84
P
Vest4
0.63
MutPred
0.79
Gain of loop (P = 0.002);
MVP
0.52
MPC
0.58
ClinPred
0.92
D
GERP RS
4.4
PromoterAI
-0.041
Neutral
Varity_R
0.51
gMVP
0.83
Mutation Taster
=57/43
polymorphism

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

Other links and lift over

dbSNP: rs1417381110; hg19: chr16-55513432; API