5-179345249-AGCG-AGCGGCG

Variant names:

• chr5-179345249-A-AGCG
• rs763392299
• NM_014244.5:c.77_79dupCGC

Variant summary

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

The NM_014244.5(ADAMTS2):​c.77_79dupCGC​(p.Pro26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,139,720 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. L27L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: ADAMTS2 NM_014244.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:1
• Conservation: PhyloP100: 0.567
• 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_79dupCGC	p.Pro26dup	conservative_inframe_insertion	Exon 1 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.77_79dupCGC	p.Pro26dup	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.77_79dupCGC	p.Pro26dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.77_79dupCGC	p.Pro26dup	conservative_inframe_insertion	Exon 1 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.77_79dupCGC	p.Pro26dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 174 AN: 144276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000819

Gnomad ASJ AF: 0.00266

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000335

Gnomad OTH AF: 0.00252

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1168 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000567 AC: 564 AN: 995350 Hom.: 0 Cov.: 30 AF XY: 0.000522 AC XY: 248 AN XY: 475366

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

African (AFR) AF: 0.00282 AC: 55 AN: 19510

American (AMR) AF: 0.00107 AC: 6 AN: 5594

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 20 AN: 9908

East Asian (EAS) AF: 0.00 AC: 0 AN: 16166

South Asian (SAS) AF: 0.0000522 AC: 1 AN: 19170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15586

Middle Eastern (MID) AF: 0.000401 AC: 1 AN: 2492

European-Non Finnish (NFE) AF: 0.000528 AC: 459 AN: 869790

Other (OTH) AF: 0.000592 AC: 22 AN: 37134

⚠️ 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 AF: 0.00120 AC: 173 AN: 144370 Hom.: 0 Cov.: 33 AF XY: 0.00113 AC XY: 79 AN XY: 70150

African (AFR) AF: 0.00319 AC: 126 AN: 39456

American (AMR) AF: 0.000750 AC: 11 AN: 14674

Ashkenazi Jewish (ASJ) AF: 0.00266 AC: 9 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4608

South Asian (SAS) AF: 0.00 AC: 0 AN: 4400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8960

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

European-Non Finnish (NFE) AF: 0.000335 AC: 22 AN: 65710

Other (OTH) AF: 0.00249 AC: 5 AN: 2008

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	Ehlers-Danlos syndrome, dermatosparaxis type (2)
-	1	-	ADAMTS2-related disorder (1)
-	1	-	Ehlers-Danlos syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=79/21	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs763392299; hg19: chr5-178772250;