chr16-55479277-T-TGCG

Position:

• chr16-55479277-T-TGCG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_004530.6(MMP2):​c.-183_-181dupCGG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000722 in 401,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: MMP2 NM_004530.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000991 (15/151370) while in subpopulation EAS AF= 0.000391 (2/5118). AF 95% confidence interval is 0.0000691. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP2	NM_004530.6	c.-183_-181dupCGG		5_prime_UTR_variant	1/13	ENST00000219070.9	NP_004521.1
MMP2	NM_001302508.1	c.-76+332_-76+334dupCGG		intron_variant			NP_001289437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070	c.-183_-181dupCGG		5_prime_UTR_variant	1/13	1	NM_004530.6	ENSP00000219070.4
MMP2	ENST00000570308.5	c.-75-3612_-75-3610dupCGG		intron_variant		1		ENSP00000461421.1
MMP2	ENST00000568715.5	c.-76+332_-76+334dupCGG		intron_variant		4		ENSP00000457949.1

Frequencies

GnomAD3 genomes AF: 0.0000992 AC: 15 AN: 151274 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000560 AC: 14 AN: 250018 Hom.: 0 Cov.: 4 AF XY: 0.0000630 AC XY: 8 AN XY: 126950

Gnomad4 AFR exome AF: 0.000171

Gnomad4 AMR exome AF: 0.000191

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000614

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0000576

Gnomad4 NFE exome AF: 0.0000445

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000991 AC: 15 AN: 151370 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73976

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000391

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000121

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multicentric Osteolysis-Nodulosis-Arthropathy (MONA) Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs567092201; hg19: chr16-55513189;