5-179345258-GGCAGCAGCAGCAGCA-GGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr5-179345258-G-GGCAGCAGCAGCAGCA
• rs568040559
• NM_014244.5:c.56_70dupTGCTGCTGCTGCTGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_014244.5(ADAMTS2):​c.56_70dupTGCTGCTGCTGCTGC​(p.Leu19_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 0.0000204 in 147,072 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 NM_014244.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.00
• Publications: 6 publications found

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), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_014244.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 11	NP_067610.1	O95450-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.56_70dupTGCTGCTGCTGCTGC	p.Leu19_Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 146980 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000212 AC: 21 AN: 989358 Hom.: 0 Cov.: 29 AF XY: 0.0000233 AC XY: 11 AN XY: 472146

African (AFR) AF: 0.000105 AC: 2 AN: 19040

American (AMR) AF: 0.00 AC: 0 AN: 5490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9740

East Asian (EAS) AF: 0.000315 AC: 5 AN: 15854

South Asian (SAS) AF: 0.00 AC: 0 AN: 18838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2440

European-Non Finnish (NFE) AF: 0.0000162 AC: 14 AN: 865856

Other (OTH) AF: 0.00 AC: 0 AN: 36820

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 147072 Hom.: 0 Cov.: 28 AF XY: 0.0000279 AC XY: 2 AN XY: 71648

African (AFR) AF: 0.0000250 AC: 1 AN: 40070

American (AMR) AF: 0.000134 AC: 2 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4946

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66382

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 36

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, dermatosparaxis type (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=72/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs568040559; hg19: chr5-178772259;