5-179128096-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014244.5(ADAMTS2):c.2480G>A(p.Arg827Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,613,704 control chromosomes in the GnomAD database, including 1,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R827W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 58 hom., cov: 32)

Exomes 𝑓: 0.033 ( 952 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.56

Publications

17 publications found

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 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

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005013287).

BP6

Variant 5-179128096-C-T is Benign according to our data. Variant chr5-179128096-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3819/152218) while in subpopulation NFE AF = 0.0365 (2483/68010). AF 95% confidence interval is 0.0353. There are 58 homozygotes in GnomAd4. There are 1772 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5 link	c.2480G>A	p.Arg827Gln	missense_variant	Exon 17 of 22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	XM_047417895.1 link	c.1985G>A	p.Arg662Gln	missense_variant	Exon 16 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1 link	c.1598G>A	p.Arg533Gln	missense_variant	Exon 15 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 link	c.2480G>A	p.Arg827Gln	missense_variant	Exon 17 of 22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000518335.3 link	c.2480G>A	p.Arg827Gln	missense_variant	Exon 17 of 21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 link	n.2480G>A		non_coding_transcript_exon_variant	Exon 17 of 21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3819

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00676

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0309

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0365

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0261

AC:

6551

AN:

251048

AF XY:

0.0263

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.0198

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0369

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0332

AC:

48523

AN:

1461486

Hom.:

952

Cov.:

AF XY:

0.0323

AC XY:

23480

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.00562

AC:

188

AN:

33480

American (AMR)

AF:

0.0212

AC:

949

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

1431

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00467

AC:

403

AN:

86258

European-Finnish (FIN)

AF:

0.0286

AC:

1515

AN:

53052

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5768

European-Non Finnish (NFE)

AF:

0.0377

AC:

41913

AN:

1111982

Other (OTH)

AF:

0.0331

AC:

1998

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

2754

5507

8261

11014

13768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1568

3136

4704

6272

7840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0251

AC:

3819

AN:

152218

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

1772

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00674

AC:

280

AN:

41536

American (AMR)

AF:

0.0256

AC:

391

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

171

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00270

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0309

AC:

328

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0365

AC:

2483

AN:

68010

Other (OTH)

AF:

0.0307

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

193

386

578

771

964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0320

Hom.:

271

Bravo

AF:

0.0255

TwinsUK

AF:

0.0348

AC:

129

ALSPAC

AF:

0.0402

AC:

155

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0377

AC:

324

ExAC

AF:

0.0252

AC:

3064

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0444

EpiControl

AF:

0.0430

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:2

Oct 31, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 22, 2021

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.2480G>A (p.Arg827Gln) results in a conservative amino acid change located in the ADAM-TS Spacer 1 domain (IPR010294) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 251048 control chromosomes in the gnomAD database, including 126 homozygotes. The observed variant frequency is approximately 9- fold 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, there are no reports of of c.2480G>A in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating an impact on protein function published in the literature. Four 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/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Ehlers-Danlos syndrome

Benign:1

Jul 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.57

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

PhyloP100

2.6

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.081

Sift

Benign

0.063

T;.

Sift4G

Benign

0.061

T;.

Polyphen

0.038

B;.

Vest4

0.10

MPC

0.48

ClinPred

0.021

GERP RS

3.4

Varity_R

0.14

gMVP

0.61

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over