5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCA

Variant names:

• chr5-179345258-G-GGCAGCA
• rs568040559
• NM_014244.5:c.65_70dupTGCTGC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_014244.5(ADAMTS2):​c.65_70dupTGCTGC​(p.Leu22_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 0.000253 in 1,136,418 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 0.00041 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.00

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-179345258-G-GGCAGCA is Benign according to our data. Variant chr5-179345258-G-GGCAGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506736.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.65_70dupTGCTGC	p.Leu22_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.65_70dupTGCTGC	p.Leu22_Leu23dup	conservative_inframe_insertion	Exon 1 of 11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.65_70dupTGCTGC	p.Leu22_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.65_70dupTGCTGC	p.Leu22_Leu23dup	conservative_inframe_insertion	Exon 1 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.65_70dupTGCTGC	p.Leu22_Leu23dup	conservative_inframe_insertion	Exon 1 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.65_70dupTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 60 AN: 146978 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000851

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.000627

Gnomad FIN AF: 0.000107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000196

Gnomad OTH AF: 0.000979

GnomAD3 exomes AF: 0.000896 AC: 1 AN: 1116 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000229 AC: 227 AN: 989348 Hom.: 0 Cov.: 29 AF XY: 0.000261 AC XY: 123 AN XY: 472142

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00170

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.000196

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000380

GnomAD4 genome AF: 0.000415 AC: 61 AN: 147070 Hom.: 0 Cov.: 28 AF XY: 0.000251 AC XY: 18 AN XY: 71648

Gnomad4 AFR AF: 0.000849

Gnomad4 AMR AF: 0.000134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00101

Gnomad4 SAS AF: 0.000628

Gnomad4 FIN AF: 0.000107

Gnomad4 NFE AF: 0.000211

Gnomad4 OTH AF: 0.000969

Bravo AF: 0.000536

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Dec 08, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADAMTS2: BS2 -

Ehlers-Danlos syndrome, dermatosparaxis type Uncertain:1

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.65_70dup, results in the insertion of 2 amino acid(s) of the ADAMTS2 protein (p.Leu22_Leu23dup), 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: 506736). 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 Benign:1

Mar 11, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs568040559; hg19: chr5-178772259;