rs863223491

chr2-189062865-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000393.5(COL5A2):c.1977G>A(p.Pro659=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL5A2 NM_000393.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.49

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-189062865-C-T is Pathogenic according to our data. Variant chr2-189062865-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 213101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189062865-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.1977G>A	p.Pro659=	splice_region_variant, synonymous_variant	29/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.1839G>A	p.Pro613=	splice_region_variant, synonymous_variant	32/57
COL5A2	XM_047443251.1	c.1839G>A	p.Pro613=	splice_region_variant, synonymous_variant	34/59
COL5A2	XM_047443252.1	c.1839G>A	p.Pro613=	splice_region_variant, synonymous_variant	33/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.1977G>A	p.Pro659=	splice_region_variant, synonymous_variant	29/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.816G>A	p.Pro272=	splice_region_variant, synonymous_variant	22/47	5
COL5A2	ENST00000470524.2	n.83G>A		splice_region_variant, non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461796 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, classic type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

May 10, 2024

This variant has been reported in the literature in at least 3 individuals with suspicion or clinical diagnoses of Ehlers-Danlos syndrome, classic type (cEDS), including as de novo in two families (Ritelli 2013 PMID: 23587214; Xu 2019 PMID: 31517854; Ma 2021 PMID: 33834621). It is not present in gnomAD, and has been submitted to ClinVar (Variation ID: 213101). Of note, this is a synonnymous variant that does not change the amino acid at this codon; however, it is located at the last nucleotide of exon 29 and computational splice prediction algorithms predict that it may weaken or abolish the donor splice site. An evaluation of this variant by cDNA sequencing from fibroblast-derived RNA supports these predictions, demonstrating that this variant results in the skipping of exon 29 (Ma 2021 PMID: 33834621). This is not expected to disrupt the reading frame but would remove 6 Gly-X-Y repeats in the encoded triple helical region which may impair the formation of type V collagen heterotrimers (Malfait 2024 PMID: 20301422). In summary, this variant is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change affects codon 659 of the COL5A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL5A2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of COL5A2-related Ehlers-Danlos syndrome (PMID: 31517854, 33834621). In at least one individual the variant was observed to be de novo. This variant is also known as c.1997G>A. ClinVar contains an entry for this variant (Variation ID: 213101). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 29, but is expected to preserve the integrity of the reading-frame (PMID: 33834621). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863223491; hg19: chr2-189927591;