rs1199481029

chr2-189064588-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_000393.5(COL5A2):c.1685G>A(p.Arg562His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R562G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.1685G>A	p.Arg562His	missense_variant	25/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.1547G>A	p.Arg516His	missense_variant	28/57
COL5A2	XM_047443251.1	c.1547G>A	p.Arg516His	missense_variant	30/59
COL5A2	XM_047443252.1	c.1547G>A	p.Arg516His	missense_variant	29/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.1685G>A	p.Arg562His	missense_variant	25/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.524G>A	p.Arg175His	missense_variant	18/47	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251256 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135818

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461706 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

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

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Apr 28, 2018

This sequence change replaces arginine with histidine at codon 562 of the COL5A2 protein (p.Arg562His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL5A2-related disease. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;T;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.72
MutPred		0.64		Loss of methylation at R562 (P = 0.0197);.;Loss of methylation at R562 (P = 0.0197);
MVP		0.88
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.33
gMVP		0.40

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: rs1199481029; hg19: chr2-189929314; COSMIC: COSV66416186; COSMIC: COSV66416186;