dbSNP rs35462609: ADAMTS2:p.Asn312Asn (chr5-179181111-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014244.5(ADAMTS2):c.936C>T(p.Asn312Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,766 control chromosomes in the GnomAD database, including 1,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 71 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1169 hom. )

Consequence

ADAMTS2
NM_014244.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.36

Publications

6 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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

ADAMTS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 5-179181111-G-A is Benign according to our data. Variant chr5-179181111-G-A is described in ClinVar as Benign. ClinVar VariationId is 353128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0264 (4011/152196) while in subpopulation NFE AF = 0.0401 (2724/67998). AF 95% confidence interval is 0.0388. There are 71 homozygotes in GnomAd4. There are 1960 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 71 AR gene

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.936C>T	p.Asn312Asn	synonymous	Exon 5 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.936C>T	p.Asn312Asn	synonymous	Exon 5 of 11	NP_067610.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.936C>T	p.Asn312Asn	synonymous	Exon 5 of 22	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	TSL:1	c.936C>T	p.Asn312Asn	synonymous	Exon 5 of 11	ENSP00000274609.5
ADAMTS2	ENST00000957641.1		c.936C>T	p.Asn312Asn	synonymous	Exon 5 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes

AF:

0.0264

AC:

4011

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00688

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00602

Gnomad FIN

AF:

0.0581

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0268

AC:

6748

AN:

251326

AF XY:

0.0269

show subpopulations

Gnomad AFR exome

AF:

0.00665

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.00824

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0603

Gnomad NFE exome

AF:

0.0388

Gnomad OTH exome

AF:

0.0271

GnomAD4 exome

AF:

0.0362

AC:

52934

AN:

1461570

Hom.:

1169

Cov.:

AF XY:

0.0355

AC XY:

25797

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.00565

AC:

189

AN:

33480

American (AMR)

AF:

0.0137

AC:

614

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00937

AC:

245

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00788

AC:

680

AN:

86256

European-Finnish (FIN)

AF:

0.0566

AC:

3017

AN:

53328

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0417

AC:

46318

AN:

1111790

Other (OTH)

AF:

0.0303

AC:

1829

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2558

5116

7673

10231

12789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1668

3336

5004

6672

8340

<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:

0.0264

AC:

4011

AN:

152196

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1960

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00686

AC:

285

AN:

41528

American (AMR)

AF:

0.0165

AC:

252

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00602

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0581

AC:

616

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0401

AC:

2724

AN:

67998

Other (OTH)

AF:

0.0289

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

203

407

610

814

1017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0351

Hom.:

Bravo

AF:

0.0233

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0375

EpiControl

AF:

0.0345

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, dermatosparaxis type (3)

not specified (2)

Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.0

(source)

DANN

Benign

0.70

PhyloP100

-1.4

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over