5-179345227-GGGCGGC-GGGCGGCGGC

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_014244.5(ADAMTS2):c.101_102insGCC(p.Pro33dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,119,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 0.117

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 5-179345227-G-GGGC is Benign according to our data. Variant chr5-179345227-G-GGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 509635.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS2	NM_014244.5	c.101_102insGCC	p.Pro33dup	inframe_insertion	1/22	ENST00000251582.12
ADAMTS2	NM_021599.4	c.101_102insGCC	p.Pro33dup	inframe_insertion	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.101_102insGCC	p.Pro33dup	inframe_insertion	1/22	1	NM_014244.5	P2
ADAMTS2	ENST00000274609.5	c.101_102insGCC	p.Pro33dup	inframe_insertion	1/11	1
ADAMTS2	ENST00000518335.3	c.101_102insGCC	p.Pro33dup	inframe_insertion	1/21	3		A2
ADAMTS2	ENST00000698889.1	c.101_102insGCC	p.Pro33dup	inframe_insertion, NMD_transcript_variant	1/21

Frequencies

GnomAD3 genomes AF: 0.000229 AC: 34 AN: 148190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000246

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: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000315

Gnomad OTH AF: 0.000979

GnomAD4 exome AF: 0.000559 AC: 543 AN: 971260 Hom.: 0 Cov.: 29 AF XY: 0.000518 AC XY: 240 AN XY: 463420

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000686

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000583

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000229 AC: 34 AN: 148292 Hom.: 0 Cov.: 32 AF XY: 0.000180 AC XY: 13 AN XY: 72288

Gnomad4 AFR AF: 0.000246

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000106

Gnomad4 NFE AF: 0.000315

Gnomad4 OTH AF: 0.000969

Bravo AF: 0.000272

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-14-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 26, 2022	This variant, c.99_101dup, results in the insertion of 1 amino acid(s) of the ADAMTS2 protein (p.Pro34dup), 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: 509635). 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 14, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2020

In-frame duplication of 1 amino acids in a repetitive region with no known function; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs770212030; hg19: chr5-178772228;