Variant chr5-179345258-G-GGCAGCAGCAGCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000251582.12(ADAMTS2):c.70_71insTGCTGCTGCTGC(p.Leu20_Leu23dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 146,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAMTS2
ENST00000251582.12 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.00

Variant links:

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.70_71insTGCTGCTGCTGC	p.Leu20_Leu23dup	inframe_insertion	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.70_71insTGCTGCTGCTGC	p.Leu20_Leu23dup	inframe_insertion	1/11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.70_71insTGCTGCTGCTGC	p.Leu20_Leu23dup	inframe_insertion	1/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.70_71insTGCTGCTGCTGC	p.Leu20_Leu23dup	inframe_insertion	1/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.70_71insTGCTGCTGCTGC	p.Leu20_Leu23dup	inframe_insertion	1/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.70_71insTGCTGCTGCTGC	p.Leu20_Leu23dup	inframe_insertion, NMD_transcript_variant	1/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

146980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000303

AC:

AN:

989358

Hom.:

Cov.:

AF XY:

0.0000402

AC XY:

AN XY:

472146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000631

Gnomad4 SAS exome

AF:

0.0000531

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000289

Gnomad4 OTH exome

AF:

0.0000815

GnomAD4 genome

AF:

0.0000204

AC:

AN:

146980

Hom.:

Cov.:

AF XY:

0.0000419

AC XY:

AN XY:

71540

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This variant, c.59_70dup, results in the insertion of 4 amino acid(s) to the ADAMTS2 protein (p.Leu20_Leu23dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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