rs1553515880

Variant names:

• chr2-189068868-G-A
• rs1553515880
• NM_000393.5:c.1175C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000393.5(COL5A2):​c.1175C>T​(p.Thr392Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.25

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1175C>T	p.Thr392Ile	missense_variant	Exon 19 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1037C>T	p.Thr346Ile	missense_variant	Exon 22 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.1037C>T	p.Thr346Ile	missense_variant	Exon 24 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.1037C>T	p.Thr346Ile	missense_variant	Exon 23 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1175C>T	p.Thr392Ile	missense_variant	Exon 19 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.359-2435C>T		intron_variant	Intron 15 of 46	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460234 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726480

Gnomad4 AFR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Feb 26, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 459724; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016) -

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

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 392 of the COL5A2 protein (p.Thr392Ile). This variant is not present in population databases (gnomAD no frequency). 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: 459724). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL5A2 protein function with a negative predictive value of 80%. 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.48	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.085	T;.
Sift4G	Benign	0.40	T;.
Polyphen		0.94	P;P
Vest4		0.41
MutPred		0.28		Loss of phosphorylation at T392 (P = 0.0036);Loss of phosphorylation at T392 (P = 0.0036);
MVP		0.61
MPC		0.95
ClinPred		0.70	D
GERP RS		5.7
Varity_R		0.094
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553515880; hg19: chr2-189933594;