rs1553515645

Variant names:

• chr2-189066435-T-A
• rs1553515645
• NM_000393.5:c.1518A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000393.5(COL5A2):​c.1518A>T​(p.Arg506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.134
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: REVEL computational evidence supports a deleterious effect, 0.683

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1518A>T	p.Arg506Ser	missense_variant	Exon 23 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1380A>T	p.Arg460Ser	missense_variant	Exon 26 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.1380A>T	p.Arg460Ser	missense_variant	Exon 28 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.1380A>T	p.Arg460Ser	missense_variant	Exon 27 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1518A>T	p.Arg506Ser	missense_variant	Exon 23 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.359-2A>T		splice_acceptor_variant, intron_variant	Intron 15 of 46	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Nov 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1518A>T (p.R506S) alteration is located in coding exon 23 of the COL5A2 gene. This alteration results from an A to T substitution at nucleotide position 1518, causing the arginine (R) at amino acid position 506 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.078
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Uncertain	0.19	D
PhyloP100		-0.13
ClinPred		0.84	D
GERP RS		-0.35
Varity_R		0.15
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs1553515645; hg19: chr2-189931161;