rs771415085

chr2-189035106-G-Achr2-189035106-G-Cchr2-189035106-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000393.5(COL5A2):c.4163C>T(p.Thr1388Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T1388N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL5A2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.4163C>T	p.Thr1388Ile	missense_variant	53/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.4025C>T	p.Thr1342Ile	missense_variant	56/57
COL5A2	XM_047443251.1	c.4025C>T	p.Thr1342Ile	missense_variant	58/59
COL5A2	XM_047443252.1	c.4025C>T	p.Thr1342Ile	missense_variant	57/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.4163C>T	p.Thr1388Ile	missense_variant	53/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.3002C>T	p.Thr1001Ile	missense_variant	46/47	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Jun 24, 2023

ClinVar contains an entry for this variant (Variation ID: 408292). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL5A2 protein function. This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1388 of the COL5A2 protein (p.Thr1388Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;T;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.6	H;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.010	D;.;.
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.58
MutPred		0.84		Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);
MVP		0.88
MPC		0.28
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs771415085; hg19: chr2-189899832;