rs243840

Variant names:

• chr16-55494247-G-A
• rs243840
• NM_004530.6:c.1472+954G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004530.6(MMP2):​c.1472+954G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 152,156 control chromosomes in the GnomAD database, including 40,182 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (40182 hom., cov: 33)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.818 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	NM_004530.6	MANE Select	c.1472+954G>A		intron	N/A	NP_004521.1	P08253-1
	MMP2	NM_001127891.3		c.1322+954G>A		intron	N/A	NP_001121363.1	P08253-3
	MMP2	NM_001302508.1		c.1244+954G>A		intron	N/A	NP_001289437.1	P08253-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP2	ENST00000219070.9	TSL:1 MANE Select	c.1472+954G>A		intron	N/A	ENSP00000219070.4	P08253-1
	MMP2	ENST00000437642.6	TSL:1	c.1322+954G>A		intron	N/A	ENSP00000394237.2	P08253-3
	MMP2	ENST00000570308.5	TSL:1	c.1244+954G>A		intron	N/A	ENSP00000461421.1	P08253-2

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108319 AN: 152038 Hom.: 40176 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.865

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.697

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.712 AC: 108353 AN: 152156 Hom.: 40182 Cov.: 33 AF XY: 0.714 AC XY: 53069 AN XY: 74376

African (AFR) AF: 0.494 AC: 20487 AN: 41480

American (AMR) AF: 0.729 AC: 11154 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3470

East Asian (EAS) AF: 0.588 AC: 3043 AN: 5172

South Asian (SAS) AF: 0.769 AC: 3703 AN: 4816

European-Finnish (FIN) AF: 0.828 AC: 8780 AN: 10598

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56024 AN: 68006

Other (OTH) AF: 0.697 AC: 1474 AN: 2114

Alfa AF: 0.800 Hom.: 24253

Bravo AF: 0.694

Asia WGS AF: 0.666 AC: 2312 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.096
DANN	Benign	0.29
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs243840; hg19: chr16-55528159;