rs12599775

Variant names:

• chr16-55489870-G-C
• rs12599775
• NM_004530.6:c.1180+46G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-55489870-G-C
• chr16-55489870-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004530.6(MMP2):​c.1180+46G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,601,162 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (116 hom., cov: 33)
  • Exomes 𝑓: 0.015 (504 hom.)
• Consequence: MMP2 NM_004530.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.14
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-55489870-G-C is Benign according to our data. Variant chr16-55489870-G-C is described in ClinVar as Benign. ClinVar VariationId is 1248285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP2	NM_004530.6	c.1180+46G>C		intron_variant	Intron 7 of 12	ENST00000219070.9	NP_004521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9	c.1180+46G>C		intron_variant	Intron 7 of 12	1	NM_004530.6	ENSP00000219070.4

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4482 AN: 152098 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.0566

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00770

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0314 AC: 7196 AN: 229068 AF XY: 0.0298

Gnomad AFR exome AF: 0.0599

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.0396

Gnomad EAS exome AF: 0.0982

Gnomad FIN exome AF: 0.00769

Gnomad NFE exome AF: 0.00726

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0149 AC: 21580 AN: 1448946 Hom.: 504 Cov.: 32 AF XY: 0.0155 AC XY: 11167 AN XY: 720316

African (AFR) AF: 0.0585 AC: 1944 AN: 33222

American (AMR) AF: 0.0619 AC: 2655 AN: 42898

Ashkenazi Jewish (ASJ) AF: 0.0402 AC: 1044 AN: 25942

East Asian (EAS) AF: 0.0942 AC: 3708 AN: 39346

South Asian (SAS) AF: 0.0404 AC: 3441 AN: 85238

European-Finnish (FIN) AF: 0.00699 AC: 355 AN: 50816

Middle Eastern (MID) AF: 0.0209 AC: 106 AN: 5074

European-Non Finnish (NFE) AF: 0.00638 AC: 7057 AN: 1106438

Other (OTH) AF: 0.0212 AC: 1270 AN: 59972

GnomAD4 genome AF: 0.0295 AC: 4488 AN: 152216 Hom.: 116 Cov.: 33 AF XY: 0.0301 AC XY: 2236 AN XY: 74402

African (AFR) AF: 0.0565 AC: 2346 AN: 41534

American (AMR) AF: 0.0409 AC: 626 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.0921 AC: 474 AN: 5144

South Asian (SAS) AF: 0.0434 AC: 209 AN: 4820

European-Finnish (FIN) AF: 0.00715 AC: 76 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00771 AC: 524 AN: 68006

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0221 Hom.: 11

Bravo AF: 0.0346

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.017
DANN	Benign	0.48
PhyloP100		-5.1
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: rs12599775; hg19: chr16-55523782;