Genetic Variant NM_004530.6:c.51C>G (chr16-55479530-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_004530.6(MMP2):c.51C>G(p.Leu17Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MMP2
NM_004530.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.162

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

MMP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP7

Synonymous conserved (PhyloP=-0.162 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6 link	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 13	ENST00000219070.9	NP_004521.1	P08253-1A0A024R6R4
MMP2	NM_001302508.1 link	c.-76+565C>G		intron_variant	Intron 1 of 12		NP_001289437.1	P08253-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMP2	ENST00000219070.9 link	c.51C>G	p.Leu17Leu	synonymous_variant	Exon 1 of 13	1	NM_004530.6	ENSP00000219070.4	P08253-1
MMP2	ENST00000570308.5 link	c.-75-3379C>G		intron_variant	Intron 2 of 13	1		ENSP00000461421.1	P08253-2
MMP2	ENST00000568715.5 link	c.-76+565C>G		intron_variant	Intron 1 of 3	4		ENSP00000457949.1	H3BV48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

85744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110470

Other (OTH)

AF:

0.00

AC:

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.4

(source)

DANN

Benign

0.58

PhyloP100

-0.16

PromoterAI

0.028

Neutral

(source)

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

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NM_004530.6:c.51C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over