rs243834

Positions:

chr16-55502775-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004530.6(MMP2):c.1770-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,611,146 control chromosomes in the GnomAD database, including 185,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15862 hom., cov: 32)

Exomes 𝑓: 0.48 ( 169406 hom. )

Consequence

MMP2
NM_004530.6 splice_region, intron

Scores

Splicing: ADA: 0.00007448

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0560

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 16-55502775-A-G is Benign according to our data. Variant chr16-55502775-A-G is described in ClinVar as [Benign]. Clinvar id is 319766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-55502775-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP2	NM_004530.6 linkuse as main transcript	c.1770-4A>G		splice_region_variant, intron_variant		ENST00000219070.9	NP_004521.1	P08253-1A0A024R6R4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP2	ENST00000219070.9 linkuse as main transcript	c.1770-4A>G		splice_region_variant, intron_variant		1	NM_004530.6	ENSP00000219070.4		P08253-1

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

68923

AN:

151824

Hom.:

15857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.384

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.437

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.530

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.450

GnomAD3 exomes

AF:

0.487

AC:

122368

AN:

251062

Hom.:

30221

AF XY:

0.489

AC XY:

66284

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.379

Gnomad AMR exome

AF:

0.481

Gnomad ASJ exome

AF:

0.446

Gnomad EAS exome

AF:

0.635

Gnomad SAS exome

AF:

0.518

Gnomad FIN exome

AF:

0.525

Gnomad NFE exome

AF:

0.470

Gnomad OTH exome

AF:

0.473

GnomAD4 exome

AF:

0.480

AC:

700877

AN:

1459206

Hom.:

169406

Cov.:

AF XY:

0.481

AC XY:

349122

AN XY:

726050

show subpopulations

Gnomad4 AFR exome

AF:

0.380

Gnomad4 AMR exome

AF:

0.479

Gnomad4 ASJ exome

AF:

0.449

Gnomad4 EAS exome

AF:

0.629

Gnomad4 SAS exome

AF:

0.517

Gnomad4 FIN exome

AF:

0.516

Gnomad4 NFE exome

AF:

0.475

Gnomad4 OTH exome

AF:

0.474

GnomAD4 genome

AF:

0.454

AC:

68947

AN:

151940

Hom.:

15862

Cov.:

AF XY:

0.458

AC XY:

33978

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.384

Gnomad4 AMR

AF:

0.451

Gnomad4 ASJ

AF:

0.437

Gnomad4 EAS

AF:

0.641

Gnomad4 SAS

AF:

0.530

Gnomad4 FIN

AF:

0.520

Gnomad4 NFE

AF:

0.470

Gnomad4 OTH

AF:

0.447

Alfa

AF:

0.464

Hom.:

27226

Bravo

AF:

0.446

Asia WGS

AF:

0.550

AC:

1916

AN:

3478

EpiCase

AF:

0.469

EpiControl

AF:

0.469

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Multicentric osteolysis nodulosis arthropathy spectrum

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.2

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000074

dbscSNV1_RF

Benign

0.0080

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over