16-55479277-TGCGGCGGCGGCGGCG-TGCGGCG

Variant names:

• chr16-55479277-TGCGGCGGCG-T
• rs567092201
• NM_004530.6:c.-189_-181delCGGCGGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004530.6(MMP2):​c.-189_-181delCGGCGGCGG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.000012 in 250,014 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MMP2 NM_004530.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.-189_-181delCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 13	ENST00000219070.9	NP_004521.1
MMP2	NM_001302508.1	c.-76+326_-76+334delCGGCGGCGG		intron_variant	Intron 1 of 12		NP_001289437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.-189_-181delCGGCGGCGG		5_prime_UTR_variant	Exon 1 of 13	1	NM_004530.6	ENSP00000219070.4
MMP2	ENST00000570308.5	c.-75-3618_-75-3610delCGGCGGCGG		intron_variant	Intron 2 of 13	1		ENSP00000461421.1
MMP2	ENST00000568715.5	c.-76+326_-76+334delCGGCGGCGG		intron_variant	Intron 1 of 3	4		ENSP00000457949.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000120 AC: 3 AN: 250014 Hom.: 0 AF XY: 0.00000788 AC XY: 1 AN XY: 126948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 5860

American (AMR) AF: 0.00 AC: 0 AN: 5234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6518

East Asian (EAS) AF: 0.00 AC: 0 AN: 16292

South Asian (SAS) AF: 0.00 AC: 0 AN: 4122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1082

European-Non Finnish (NFE) AF: 0.0000111 AC: 2 AN: 179682

Other (OTH) AF: 0.0000721 AC: 1 AN: 13866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7

Splicing

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

Other links and lift over

dbSNP: rs567092201; hg19: chr16-55513189;