chr16-55479277-TGCG-T

Variant names:

• chr16-55479277-TGCG-T
• rs567092201
• NM_004530.6:c.-183_-181delCGG

Variant summary

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

The NM_004530.6(MMP2):​c.-183_-181delCGG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0121 in 377,384 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: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.020 (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: Variant has high frequency in the AMR (0.0195) population. However there is too low homozygotes in high coverage region: (expected more than 13, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.-183_-181delCGG		5_prime_UTR_variant	Exon 1 of 13	ENST00000219070.9	NP_004521.1
MMP2	NM_001302508.1	c.-76+332_-76+334delCGG		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.-183_-181delCGG		5_prime_UTR_variant	Exon 1 of 13	1	NM_004530.6	ENSP00000219070.4
MMP2	ENST00000570308.5	c.-75-3612_-75-3610delCGG		intron_variant	Intron 2 of 13	1		ENSP00000461421.1
MMP2	ENST00000568715.5	c.-76+332_-76+334delCGG		intron_variant	Intron 1 of 3	4		ENSP00000457949.1

Frequencies

GnomAD3 genomes AF: 0.0000661 AC: 10 AN: 151184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000967

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0202 AC: 4566 AN: 226104 Hom.: 0 AF XY: 0.0208 AC XY: 2384 AN XY: 114550

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

African (AFR) AF: 0.0186 AC: 98 AN: 5276

American (AMR) AF: 0.0224 AC: 104 AN: 4642

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 110 AN: 5762

East Asian (EAS) AF: 0.0188 AC: 270 AN: 14374

South Asian (SAS) AF: 0.0184 AC: 70 AN: 3804

European-Finnish (FIN) AF: 0.0230 AC: 352 AN: 15304

Middle Eastern (MID) AF: 0.0159 AC: 15 AN: 942

European-Non Finnish (NFE) AF: 0.0201 AC: 3288 AN: 163604

Other (OTH) AF: 0.0209 AC: 259 AN: 12396

⚠️ 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 AF: 0.0000661 AC: 10 AN: 151280 Hom.: 0 Cov.: 32 AF XY: 0.0000676 AC XY: 5 AN XY: 73924

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

African (AFR) AF: 0.0000726 AC: 3 AN: 41350

American (AMR) AF: 0.0000657 AC: 1 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.0000967 AC: 1 AN: 10346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000739 AC: 5 AN: 67704

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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
Mutation Taster		=288/12	polymorphism

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: rs567092201; hg19: chr16-55513189; COSMIC: COSV54601023; COSMIC: COSV54601023;