Genetic Variant ADAMTS2:p.Leu19_Leu23del (chr5-179345258-GGCAGCAGCAGCAGCA-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_014244.5(ADAMTS2):c.56_70delTGCTGCTGCTGCTGC(p.Leu19_Leu23del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 989,358 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.38

Publications

0 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), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ADAMTS2 links:

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ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.56_70delTGCTGCTGCTGCTGC	p.Leu19_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 link	c.56_70delTGCTGCTGCTGCTGC	p.Leu19_Leu23del	disruptive_inframe_deletion	Exon 1 of 11		NP_067610.1	O95450-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 link	c.56_70delTGCTGCTGCTGCTGC	p.Leu19_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 link	c.56_70delTGCTGCTGCTGCTGC	p.Leu19_Leu23del	disruptive_inframe_deletion	Exon 1 of 11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 link	c.56_70delTGCTGCTGCTGCTGC	p.Leu19_Leu23del	disruptive_inframe_deletion	Exon 1 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.56_70delTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000101

AC:

AN:

989358

Hom.:

AF XY:

0.00

AC XY:

AN XY:

472146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19040

American (AMR)

AF:

0.00

AC:

AN:

5490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9740

East Asian (EAS)

AF:

0.00

AC:

AN:

15854

South Asian (SAS)

AF:

0.00

AC:

AN:

18838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2440

European-Non Finnish (NFE)

AF:

0.00000115

AC:

AN:

865856

Other (OTH)

AF:

0.00

AC:

AN:

36820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over