5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCA

Position:

chr5-179345258-GGCAGCAGCAGCA-GGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000251582.12(ADAMTS2):c.70_71insTGC(p.Leu23dup) variant causes a 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
ENST00000251582.12 inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.70_71insTGC	p.Leu23dup	inframe_insertion	1/22	ENST00000251582.12	NP_055059.2
ADAMTS2	NM_021599.4 linkuse as main transcript	c.70_71insTGC	p.Leu23dup	inframe_insertion	1/11		NP_067610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.70_71insTGC	p.Leu23dup	inframe_insertion	1/22	1	NM_014244.5	ENSP00000251582	P2	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.70_71insTGC	p.Leu23dup	inframe_insertion	1/11	1		ENSP00000274609		O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.70_71insTGC	p.Leu23dup	inframe_insertion	1/21	3		ENSP00000489888	A2
ADAMTS2	ENST00000698889.1 linkuse as main transcript	c.70_71insTGC	p.Leu23dup	inframe_insertion, NMD_transcript_variant	1/21			ENSP00000514008

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

25853

AN:

146894

Hom.:

2397

Cov.:

show subpopulations

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.:

AF XY:

0.168

AC XY:

114

AN XY:

680

show subpopulations

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.:

AF XY:

0.138

AC XY:

65035

AN XY:

471428

show subpopulations

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.:

AF XY:

0.184

AC XY:

13156

AN XY:

71614

show subpopulations

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

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:5

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	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 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2018	- -
Benign, flagged submission	clinical testing	GeneDx	Sep 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over