rs768322852

chr2-189064559-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_000393.5(COL5A2):c.1714C>T(p.Arg572Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000548 in 1,460,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R572Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense, splice_region
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.62

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.1714C>T	p.Arg572Trp	missense_variant, splice_region_variant	25/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.1576C>T	p.Arg526Trp	missense_variant, splice_region_variant	28/57
COL5A2	XM_047443251.1	c.1576C>T	p.Arg526Trp	missense_variant, splice_region_variant	30/59
COL5A2	XM_047443252.1	c.1576C>T	p.Arg526Trp	missense_variant, splice_region_variant	29/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.1714C>T	p.Arg572Trp	missense_variant, splice_region_variant	25/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.553C>T	p.Arg185Trp	missense_variant, splice_region_variant	18/47	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251024 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460138 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726516

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 19, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with COL5A2-related disease. This variant is present in population databases (rs768322852, ExAC 0.01%). This sequence change replaces arginine with tryptophan at codon 572 of the COL5A2 protein (p.Arg572Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;T;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.76
MutPred		0.65		Loss of methylation at R572 (P = 0.0112);.;Loss of methylation at R572 (P = 0.0112);
MVP		0.93
MPC		0.94
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.68
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.090		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: rs768322852; hg19: chr2-189929285; COSMIC: COSV66411238; COSMIC: COSV66411238;