5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCA

Variant names:

• chr5-179345258-G-GGCA
• rs568040559
• NM_014244.5:c.68_70dupTGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014244.5(ADAMTS2):​c.68_70dupTGC​(p.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 0.143 in 1,134,850 control chromosomes in the GnomAD database, including 8,203 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2398 hom., cov: 28)
  • Exomes 𝑓: 0.14 (5805 hom.)
• Consequence: ADAMTS2 NM_014244.5 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• 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 Benign. Variant got -16 ACMG points.

• BP6: Variant 5-179345258-G-GGCA is Benign according to our data. Variant chr5-179345258-G-GGCA is described in ClinVar as [Benign]. Clinvar id is 353147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4	c.68_70dupTGC	p.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.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 11	1		ENSP00000274609.5
ADAMTS2	ENST00000518335.3	c.68_70dupTGC	p.Leu23dup	conservative_inframe_insertion	Exon 1 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.68_70dupTGC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 25853 AN: 146894 Hom.: 2397 Cov.: 28

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0918

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.128

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.159 AC: 177 AN: 1116 Hom.: 18 AF XY: 0.168 AC XY: 114 AN XY: 680

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.400

Gnomad SAS exome AF: 0.339

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.138 AC: 136367 AN: 987864 Hom.: 5805 Cov.: 29 AF XY: 0.138 AC XY: 65035 AN XY: 471428

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.176 AC: 25877 AN: 146986 Hom.: 2398 Cov.: 28 AF XY: 0.184 AC XY: 13156 AN XY: 71614

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.158

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:5

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

South Asian population allele frequency is 25.41% (rs193247334, 38/112 alleles, 8 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jul 10, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADAMTS2 c.68_70dupTGC (p.Leu23dup) results in an in-frame insertion that is predicted to insert one amino acid into the encoded protein. The variant allele was found at a frequency of 0.17 in 28092 control chromosomes in the gnomAD database, including 419 homozygotes. The observed variant frequency is approximately 60-fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.68_70dupTGC in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2018

GeneDx

Significance: Benign

Review Status: flagged submission

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;