rs1862211

Positions:

• chr5-179137812-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014244.5(ADAMTS2):​c.1908C>T​(p.His636His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,578,886 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (232 hom., cov: 34)
  • Exomes 𝑓: 0.0029 (174 hom.)
• Consequence: ADAMTS2 NM_014244.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.277

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-179137812-G-A is Benign according to our data. Variant chr5-179137812-G-A is described in ClinVar as [Benign]. Clinvar id is 353117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179137812-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.277 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.1908C>T	p.His636His	synonymous_variant	12/22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1413C>T	p.His471His	synonymous_variant	11/21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1026C>T	p.His342His	synonymous_variant	10/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.1908C>T	p.His636His	synonymous_variant	12/22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.1908C>T	p.His636His	synonymous_variant	12/21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.1908C>T		non_coding_transcript_exon_variant	12/21			ENSP00000514008.1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4196 AN: 151916 Hom.: 226 Cov.: 34

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.00658 AC: 1274 AN: 193706 Hom.: 53 AF XY: 0.00491 AC XY: 514 AN XY: 104646

Gnomad AFR exome AF: 0.0964

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000161

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00286 AC: 4085 AN: 1426850 Hom.: 174 Cov.: 42 AF XY: 0.00240 AC XY: 1695 AN XY: 707012

Gnomad4 AFR exome AF: 0.0983

Gnomad4 AMR exome AF: 0.00548

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000224

Gnomad4 OTH exome AF: 0.00647

GnomAD4 genome AF: 0.0278 AC: 4233 AN: 152036 Hom.: 232 Cov.: 34 AF XY: 0.0265 AC XY: 1974 AN XY: 74356

Gnomad4 AFR AF: 0.0954

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0170 Hom.: 48

Bravo AF: 0.0313

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Benign:3

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	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2016

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. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.62

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

LitVar

Other links and lift over

dbSNP: rs1862211; hg19: chr5-178564813;