rs763392299

Variant names:

• chr5-179345249-AGCG-A
• rs763392299
• NM_014244.5:c.77_79delCGC

Your query was ambiguous. Multiple possible variants found:

• chr5-179345249-AGCG-A
• chr5-179345249-AGCG-AGCGGCG
• chr5-179345249-AGCG-AGCGGCGGCG

Variant summary

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

The NM_014244.5(ADAMTS2):​c.77_79delCGC​(p.Pro26del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000834 in 995,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P26P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.33
• Publications: 1 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.77_79delCGC	p.Pro26del	disruptive_inframe_deletion	Exon 1 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.77_79delCGC	p.Pro26del	disruptive_inframe_deletion	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.77_79delCGC	p.Pro26del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.77_79delCGC	p.Pro26del	disruptive_inframe_deletion	Exon 1 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.77_79delCGC	p.Pro26del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00171 AC: 2 AN: 1168 AF XY: 0.00149

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000834 AC: 83 AN: 995228 Hom.: 0 AF XY: 0.0000799 AC XY: 38 AN XY: 475304

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000513 AC: 1 AN: 19508

American (AMR) AF: 0.000537 AC: 3 AN: 5590

Ashkenazi Jewish (ASJ) AF: 0.000101 AC: 1 AN: 9904

East Asian (EAS) AF: 0.00 AC: 0 AN: 16158

South Asian (SAS) AF: 0.0000522 AC: 1 AN: 19166

European-Finnish (FIN) AF: 0.000128 AC: 2 AN: 15578

Middle Eastern (MID) AF: 0.000402 AC: 1 AN: 2490

European-Non Finnish (NFE) AF: 0.0000851 AC: 74 AN: 869702

Other (OTH) AF: 0.00 AC: 0 AN: 37132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Ehlers-Danlos syndrome, dermatosparaxis type (2)
-	1	-	Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs763392299; hg19: chr5-178772250;