Genetic Variant MMP2:p.Leu10Leu (chr16-55479509-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_004530.6(MMP2):c.30C>T(p.Leu10Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,445,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MMP2
NM_004530.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.50

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 16-55479509-C-T is Benign according to our data. Variant chr16-55479509-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 746207.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.5 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6 link	c.30C>T	p.Leu10Leu	synonymous_variant	Exon 1 of 13	ENST00000219070.9	NP_004521.1	P08253-1A0A024R6R4
MMP2	NM_001302508.1 link	c.-76+544C>T		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.30C>T	p.Leu10Leu	synonymous_variant	Exon 1 of 13	1	NM_004530.6	ENSP00000219070.4	P08253-1
MMP2	ENST00000570308.5 link	c.-75-3400C>T		intron_variant	Intron 2 of 13	1		ENSP00000461421.1	P08253-2
MMP2	ENST00000568715.5 link	c.-76+544C>T		intron_variant	Intron 1 of 3	4		ENSP00000457949.1	H3BV48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000464

AC:

AN:

215364

AF XY:

0.00000842

show subpopulations

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:

0.00000277

AC:

AN:

1445870

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33090

American (AMR)

AF:

0.00

AC:

AN:

42864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25772

East Asian (EAS)

AF:

0.00

AC:

AN:

38872

South Asian (SAS)

AF:

0.0000355

AC:

AN:

84534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104800

Other (OTH)

AF:

0.00

AC:

AN:

59612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.7

(source)

DANN

Benign

0.87

PhyloP100

-2.5

PromoterAI

0.0068

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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16-55479509-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over