rs146217716
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014244.5(ADAMTS2):c.655C>T(p.Pro219Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,611,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000043 ( 0 hom. )
Consequence
ADAMTS2
NM_014244.5 missense
NM_014244.5 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: 5.25
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11153492).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADAMTS2 | NM_014244.5 | c.655C>T | p.Pro219Ser | missense_variant | 3/22 | ENST00000251582.12 | NP_055059.2 | |
ADAMTS2 | NM_021599.4 | c.655C>T | p.Pro219Ser | missense_variant | 3/11 | NP_067610.1 | ||
ADAMTS2 | XM_047417895.1 | c.160C>T | p.Pro54Ser | missense_variant | 2/21 | XP_047273851.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADAMTS2 | ENST00000251582.12 | c.655C>T | p.Pro219Ser | missense_variant | 3/22 | 1 | NM_014244.5 | ENSP00000251582 | P2 | |
ADAMTS2 | ENST00000274609.5 | c.655C>T | p.Pro219Ser | missense_variant | 3/11 | 1 | ENSP00000274609 | |||
ADAMTS2 | ENST00000518335.3 | c.655C>T | p.Pro219Ser | missense_variant | 3/21 | 3 | ENSP00000489888 | A2 | ||
ADAMTS2 | ENST00000698889.1 | c.655C>T | p.Pro219Ser | missense_variant, NMD_transcript_variant | 3/21 | ENSP00000514008 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249562Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135108
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GnomAD4 exome AF: 0.0000432 AC: 63AN: 1459614Hom.: 0 Cov.: 32 AF XY: 0.0000482 AC XY: 35AN XY: 726202
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74290
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 08, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 219 of the ADAMTS2 protein (p.Pro219Ser). This variant is present in population databases (rs146217716, gnomAD 0.007%). 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: 419919). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. - |
ADAMTS2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 17, 2024 | The ADAMTS2 c.655C>T variant is predicted to result in the amino acid substitution p.Pro219Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2017 | The P219S variant in the ADAMTS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, in association with dermatosparaxis type EDS to our knowledge. The P219S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P219S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret P219S as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Benign
T;.;T
Sift4G
Benign
T;.;T
Polyphen
B;.;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at