chr5-179345261-A-G

Variant names:

• chr5-179345261-A-G
• rs565885690
• NM_014244.5:c.68T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014244.5(ADAMTS2):​c.68T>C​(p.Leu23Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 939,412 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L23L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (32 hom.)
• Consequence: ADAMTS2 NM_014244.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.273
• Publications: 4 publications found

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), G2P, Orphanet, Illumina, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006041169).
• BP6: Variant 5-179345261-A-G is Benign according to our data. Variant chr5-179345261-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372811.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00704 (1015/144088) while in subpopulation NFE AF = 0.0107 (701/65512). AF 95% confidence interval is 0.01. There are 7 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.68T>C	p.Leu23Pro	missense	Exon 1 of 22	NP_055059.2	O95450-1
	ADAMTS2	NM_021599.4		c.68T>C	p.Leu23Pro	missense	Exon 1 of 11	NP_067610.1	O95450-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS2	ENST00000251582.12	TSL:1 MANE Select	c.68T>C	p.Leu23Pro	missense	Exon 1 of 22	ENSP00000251582.7	O95450-1
	ADAMTS2	ENST00000274609.5	TSL:1	c.68T>C	p.Leu23Pro	missense	Exon 1 of 11	ENSP00000274609.5	O95450-2
	ADAMTS2	ENST00000957641.1		c.68T>C	p.Leu23Pro	missense	Exon 1 of 22	ENSP00000627700.1

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1015 AN: 144002 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00690

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.00548

Gnomad MID AF: 0.0170

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00422 AC: 5 AN: 1186 AF XY: 0.00554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00651

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0107 AC: 8482 AN: 795324 Hom.: 32 Cov.: 29 AF XY: 0.0107 AC XY: 4033 AN XY: 378562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00221 AC: 32 AN: 14466

American (AMR) AF: 0.00752 AC: 29 AN: 3858

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 163 AN: 7334

East Asian (EAS) AF: 0.00 AC: 0 AN: 12576

South Asian (SAS) AF: 0.00222 AC: 34 AN: 15316

European-Finnish (FIN) AF: 0.00858 AC: 94 AN: 10960

Middle Eastern (MID) AF: 0.0257 AC: 50 AN: 1942

European-Non Finnish (NFE) AF: 0.0111 AC: 7773 AN: 700144

Other (OTH) AF: 0.0107 AC: 307 AN: 28728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00704 AC: 1015 AN: 144088 Hom.: 7 Cov.: 32 AF XY: 0.00655 AC XY: 461 AN XY: 70350

African (AFR) AF: 0.00177 AC: 68 AN: 38404

American (AMR) AF: 0.00689 AC: 101 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 56 AN: 3292

East Asian (EAS) AF: 0.00 AC: 0 AN: 4960

South Asian (SAS) AF: 0.00273 AC: 13 AN: 4766

European-Finnish (FIN) AF: 0.00548 AC: 51 AN: 9302

Middle Eastern (MID) AF: 0.0182 AC: 5 AN: 274

European-Non Finnish (NFE) AF: 0.0107 AC: 701 AN: 65512

Other (OTH) AF: 0.00992 AC: 20 AN: 2016

Alfa AF: 0.00788 Hom.: 0

Bravo AF: 0.00669

ExAC AF: 0.0000991 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	2	Ehlers-Danlos syndrome, dermatosparaxis type (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.52
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.27
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.12
Sift	Benign	0.092	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.37
MVP		0.54
MPC		0.65
ClinPred		0.073	T
GERP RS		-1.1
PromoterAI		-0.0019	Neutral
Varity_R		0.22
gMVP		0.64
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs565885690; hg19: chr5-178772262; COSMIC: COSV51082143;