5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCA

Position:

chr5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The ENST00000251582.12(ADAMTS2):c.70_71insTGCTGC(p.Leu22_Leu23dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,136,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ADAMTS2
ENST00000251582.12 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 5-179345258-G-GGCAGCA is Benign according to our data. Variant chr5-179345258-G-GGCAGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506736.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.70_71insTGCTGC	p.Leu22_Leu23dup	inframe_insertion	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.70_71insTGCTGC	p.Leu22_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_71insTGCTGC	p.Leu22_Leu23dup	inframe_insertion	1/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.70_71insTGCTGC	p.Leu22_Leu23dup	inframe_insertion	1/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.70_71insTGCTGC	p.Leu22_Leu23dup	inframe_insertion	1/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.70_71insTGCTGC	p.Leu22_Leu23dup	inframe_insertion, NMD_transcript_variant	1/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

146978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000851

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00101

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.000107

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000196

Gnomad OTH

AF:

0.000979

GnomAD3 exomes

AF:

0.000896

AC:

AN:

1116

Hom.:

AF XY:

0.00

AC XY:

AN XY:

680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000229

AC:

227

AN:

989348

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

123

AN XY:

472142

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.000182

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00170

Gnomad4 SAS exome

AF:

0.000212

Gnomad4 FIN exome

AF:

0.000196

Gnomad4 NFE exome

AF:

0.000180

Gnomad4 OTH exome

AF:

0.000380

GnomAD4 genome

AF:

0.000415

AC:

AN:

147070

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

AN XY:

71648

show subpopulations

Gnomad4 AFR

AF:

0.000849

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00101

Gnomad4 SAS

AF:

0.000628

Gnomad4 FIN

AF:

0.000107

Gnomad4 NFE

AF:

0.000211

Gnomad4 OTH

AF:

0.000969

Bravo

AF:

0.000536

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ADAMTS2: BS2 -

Ehlers-Danlos syndrome, dermatosparaxis type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2022

This variant, c.65_70dup, results in the insertion of 2 amino acid(s) of the ADAMTS2 protein (p.Leu22_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 poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 506736). 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. -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 11, 2021

- -

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