Genetic Variant ADAMTS2:p.Leu21_Leu23del (chr5-179345258-GGCAGCAGCA-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014244.5(ADAMTS2):c.62_70delTGCTGCTGC(p.Leu21_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 0.0000101 in 989,342 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.38

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), 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.62_70delTGCTGCTGC	p.Leu21_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 link	c.62_70delTGCTGCTGC	p.Leu21_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.62_70delTGCTGCTGC	p.Leu21_Leu23del	disruptive_inframe_deletion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 link	c.62_70delTGCTGCTGC	p.Leu21_Leu23del	disruptive_inframe_deletion	Exon 1 of 11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 link	c.62_70delTGCTGCTGC	p.Leu21_Leu23del	disruptive_inframe_deletion	Exon 1 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.62_70delTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000101

AC:

AN:

989342

Hom.:

AF XY:

0.00000635

AC XY:

AN XY:

472138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19040

American (AMR)

AF:

0.00

AC:

AN:

5488

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:

0.0000115

AC:

AN:

865844

Other (OTH)

AF:

0.00

AC:

AN:

36818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

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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5-179345258-GGCAGCAGCAGCAGCA-GGCAGCA

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