NM_000393.5:c.4163C>T

Variant names:

• chr2-189035106-G-A
• rs771415085
• NM_000393.5:c.4163C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 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
• Publications: 0 publications found

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]

COL5A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.4163C>T	p.Thr1388Ile	missense_variant	Exon 53 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.4025C>T	p.Thr1342Ile	missense_variant	Exon 56 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.4025C>T	p.Thr1342Ile	missense_variant	Exon 58 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.4025C>T	p.Thr1342Ile	missense_variant	Exon 57 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.4163C>T	p.Thr1388Ile	missense_variant	Exon 53 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.3002C>T	p.Thr1001Ile	missense_variant	Exon 46 of 47	5		ENSP00000482184.1

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

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408292). 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. 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	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
LIST_S2	Uncertain	0.97	.;D;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
PhyloP100		6.8
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
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs771415085; hg19: chr2-189899832;