rs243864

Variant names:

• chr16-55478410-T-G
• rs243864
• ENST00000570308.5:c.-75-4499T>G

Variant summary

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

The ENST00000570308.5(MMP2):​c.-75-4499T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,156 control chromosomes in the GnomAD database, including 3,305 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 0.19 (3305 hom., cov: 32)
• Consequence: MMP2 ENST00000570308.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.512
• Publications: 54 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000570308.5	c.-75-4499T>G		intron_variant	Intron 2 of 13	1		ENSP00000461421.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28693 AN: 152038 Hom.: 3308 Cov.: 32

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.189 AC: 28692 AN: 152156 Hom.: 3305 Cov.: 32 AF XY: 0.190 AC XY: 14114 AN XY: 74406

African (AFR) AF: 0.0646 AC: 2683 AN: 41534

American (AMR) AF: 0.213 AC: 3257 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 689 AN: 3470

East Asian (EAS) AF: 0.106 AC: 545 AN: 5164

South Asian (SAS) AF: 0.154 AC: 740 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3067 AN: 10596

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17049 AN: 67970

Other (OTH) AF: 0.183 AC: 388 AN: 2116

Alfa AF: 0.235 Hom.: 4910

Bravo AF: 0.176

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.78
PhyloP100		0.51
PromoterAI		0.027	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs243864; hg19: chr16-55512322;