chr5-179345258-G-GGCAGCAGCA

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP3BP6

The NM_014244.5(ADAMTS2):c.62_70dupTGCTGCTGC(p.Leu21_Leu23dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000598 in 1,136,338 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 0.000075 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.00

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, dermatosparaxis type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Illumina, Genomics England PanelApp

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_014244.5

BP6

Variant 5-179345258-G-GGCAGCAGCA is Benign according to our data. Variant chr5-179345258-G-GGCAGCAGCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 515946.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.62_70dupTGCTGCTGC	p.Leu21_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.62_70dupTGCTGCTGC	p.Leu21_Leu23dup	conservative_inframe_insertion	Exon 1 of 11	NP_067610.1	O95450-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.62_70dupTGCTGCTGC	p.Leu21_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5	TSL:1	c.62_70dupTGCTGCTGC	p.Leu21_Leu23dup	conservative_inframe_insertion	Exon 1 of 11	ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000957641.1		c.62_70dupTGCTGCTGC	p.Leu21_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes

AF:

0.0000748

AC:

AN:

146980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000751

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000120

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000576

AC:

AN:

989358

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

472146

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

19040

American (AMR)

AF:

0.00

AC:

AN:

5490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9740

East Asian (EAS)

AF:

0.000189

AC:

AN:

15854

South Asian (SAS)

AF:

0.000159

AC:

AN:

18838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15280

Middle Eastern (MID)

AF:

0.000410

AC:

AN:

2440

European-Non Finnish (NFE)

AF:

0.0000531

AC:

AN:

865856

Other (OTH)

AF:

0.0000272

AC:

AN:

36820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000748

AC:

AN:

146980

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

71540

show subpopulations

African (AFR)

AF:

0.0000751

AC:

AN:

39970

American (AMR)

AF:

0.00

AC:

AN:

14908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4958

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.000120

AC:

AN:

66392

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, dermatosparaxis type (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=72/28

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over