5-179345227-G-GGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_014244.5(ADAMTS2):c.99_101dupGCC(p.Pro34dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,119,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: 0.117

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_014244.5

BP6

Variant 5-179345227-G-GGGC is Benign according to our data. Variant chr5-179345227-G-GGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 509635.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	NM_014244.5	MANE Select	c.99_101dupGCC	p.Pro34dup	disruptive_inframe_insertion	Exon 1 of 22	NP_055059.2
	ADAMTS2	NM_021599.4		c.99_101dupGCC	p.Pro34dup	disruptive_inframe_insertion	Exon 1 of 11	NP_067610.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.99_101dupGCC	p.Pro34dup	disruptive_inframe_insertion	Exon 1 of 22	ENSP00000251582.7
ADAMTS2	ENST00000274609.5	TSL:1	c.99_101dupGCC	p.Pro34dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000274609.5
ADAMTS2	ENST00000518335.3	TSL:3	c.99_101dupGCC	p.Pro34dup	disruptive_inframe_insertion	Exon 1 of 21	ENSP00000489888.2

Frequencies

GnomAD3 genomes

AF:

0.000229

AC:

AN:

148190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000106

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000315

Gnomad OTH

AF:

0.000979

GnomAD2 exomes

AF:

0.00

AC:

AN:

748

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:

0.000559

AC:

543

AN:

971260

Hom.:

Cov.:

AF XY:

0.000518

AC XY:

240

AN XY:

463420

show subpopulations

African (AFR)

AF:

0.000211

AC:

AN:

18938

American (AMR)

AF:

0.00

AC:

AN:

5112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9396

East Asian (EAS)

AF:

0.0000686

AC:

AN:

14578

South Asian (SAS)

AF:

0.00

AC:

AN:

18550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2390

European-Non Finnish (NFE)

AF:

0.000583

AC:

497

AN:

852002

Other (OTH)

AF:

0.00114

AC:

AN:

35908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000229

AC:

AN:

148292

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

72288

show subpopulations

African (AFR)

AF:

0.000246

AC:

AN:

40682

American (AMR)

AF:

0.00

AC:

AN:

14972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3424

East Asian (EAS)

AF:

0.00

AC:

AN:

5032

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.000106

AC:

AN:

9418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000315

AC:

AN:

66738

Other (OTH)

AF:

0.000969

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000272

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, dermatosparaxis type (3)

Ehlers-Danlos syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=68/32

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over