5-179345228-G-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA

Variant names:

• chr5-179345228-G-GGCGGCGGCGGCGGCGGCAGGAGCGGCGGCGGCGGCGGCAGGA
• rs1064794627
• NM_014244.5:c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC

Variant summary

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

The NM_014244.5(ADAMTS2):​c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC​(p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 147,326 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 (★). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAMTS2 NM_014244.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 0 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), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	Exon 1 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	Exon 1 of 11	NP_067610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	Exon 1 of 22	ENSP00000251582.7
	ADAMTS2	ENST00000274609.5	TSL:1	c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	Exon 1 of 11	ENSP00000274609.5
	ADAMTS2	ENST00000957641.1		c.100_101insTCCTGCCGCCGCCGCCGCCGCTCCTGCCGCCGCCGCCGCCGC	p.Pro33_Pro34insLeuLeuProProProProProLeuLeuProProProProPro	conservative_inframe_insertion	Exon 1 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147326 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000107 AC: 1 AN: 934818 Hom.: 0 Cov.: 30 AF XY: 0.00000225 AC XY: 1 AN XY: 445130

African (AFR) AF: 0.00 AC: 0 AN: 18142

American (AMR) AF: 0.00 AC: 0 AN: 4576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8554

East Asian (EAS) AF: 0.00 AC: 0 AN: 12708

South Asian (SAS) AF: 0.00 AC: 0 AN: 18024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2244

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 824070

Other (OTH) AF: 0.00 AC: 0 AN: 34062

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147326 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 71752

African (AFR) AF: 0.00 AC: 0 AN: 40190

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000300 AC: 2 AN: 66570

Other (OTH) AF: 0.00 AC: 0 AN: 2026

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, dermatosparaxis type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=85/15	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1064794627; hg19: chr5-178772229;