5-83536654-TCTTAATTTTACTCTTTTTGCAGTTCACACAAAGATGAATTCCTGCACTTCAAGATTACATTGTATATGTGATTCCTTGCTTCATTTTAAGGACTATGTTGTTTTCTTAAATGTGTTGATGAGTCTTTATAACCTGTTTTAATAATGTTAAATTGAATTCATTTTTCTTATTGTTAATACAAAAACAGTAAATTTGAAGACTGAGAACCATATAAGAGGGTGATTGCACTTATTATGAAAAGATTTGAATCCTTCTTTGTGTGTGTGGGTGTGACCAGCCTTGCTATCAATTTCTTCTGTCATACACTGCCAAATTTTCTATTTAAGTATTGTGAAAACTCTGTTTTTTTCAGGTCGAATGAGTGATTTGAGTGTAATTGGTCATCCAATAGATTCAGAATCTAAAGAAGATGAACCTTGTAGTGAAGAAACAGATCCAGTGCATGATCTAATGGCTGAAATTTTACCTGAATTCCCTGACATAATTGAAATAGACCTATACCACAGTGAAGAAAATGAAGAAGAAGAAGAAGAGTGTGCAAATGCTACTGATGTGACAACCACCCCATCTGTGCAGTACATAAATGGGAAGCATCTCGTTACCACTGTGCCCAAGGACCCAGAAGCTGCAGAAGCTAGGCGTGGCCAGTTTGAAAGTGTTGCACCTTCTCAGAATTTCTCGGACAGCTCTGAAAGTGATACTCATCCATTTGTAATAGCCAAAACGGAATTGTCTACTGCTGTGCAACCTAATGAATCTACAGAAACAACTGAGTCTCTTGAAGTTACATGGAAGCCTGAGACTTACC-T

Variant names:

• chr5-83536654-TCTTAATTTTACTCTTTTTGCAGTTCACACAAAGATGAATTCCTGCACTTCAAGATTACATTGTATATGTGATTCCTTGCTTCATTTTAAGGACTATGTTGTTTTCTTAAATGTGTTGATGAGTCTTTATAACCTGTTTTAATAATGTTAAATTGAATTCATTTTTCTTATTGTTAATACAAAAACAGTAAATTTGAAGACTGAGAACCATATAAGAGGGTGATTGCACTTATTATGAAAAGATTTGAATCCTTCTTTGTGTGTGTGGGTGTGACCAGCCTTGCTATCAATTTCTTCTGTCATACACTGCCAAATTTTCTATTTAAGTATTGTGAAAACTCTGTTTTTTTCAGGTCGAATGAGTGATTTGAGTGTAATTGGTCATCCAATAGATTCAGAATCTAAAGAAGATGAACCTTGTAGTGAAGAAACAGATCCAGTGCATGATCTAATGGCTGAAATTTTACCTGAATTCCCTGACATAATTGAAATAGACCTATACCACAGTGAAGAAAATGAAGAAGAAGAAGAAGAGTGTGCAAATGCTACTGATGTGACAACCACCCCATCTGTGCAGTACATAAATGGGAAGCATCTCGTTACCACTGTGCCCAAGGACCCAGAAGCTGCAGAAGCTAGGCGTGGCCAGTTTGAAAGTGTTGCACCTTCTCAGAATTTCTCGGACAGCTCTGAAAGTGATACTCATCCATTTGTAATAGCCAAAACGGAATTGTCTACTGCTGTGCAACCTAATGAATCTACAGAAACAACTGAGTCTCTTGAAGTTACATGGAAGCCTGAGACTTACC-T
• NM_004385.5:c.4004-350_4461del

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004385.5(VCAN):​c.4004-350_4461del​(p.Arg1336fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCAN NM_004385.5 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.05

Genes affected

VCAN (HGNC:2464): (versican) This gene is a member of the aggrecan/versican proteoglycan family. The protein encoded is a large chondroitin sulfate proteoglycan and is a major component of the extracellular matrix. This protein is involved in cell adhesion, proliferation, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance. Mutations in this gene are the cause of Wagner syndrome type 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

VCAN-AS1 (HGNC:40163): (VCAN antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-83536654-TCTTAATTTTACTCTTTTTGCAGTTCACACAAAGATGAATTCCTGCACTTCAAGATTACATTGTATATGTGATTCCTTGCTTCATTTTAAGGACTATGTTGTTTTCTTAAATGTGTTGATGAGTCTTTATAACCTGTTTTAATAATGTTAAATTGAATTCATTTTTCTTATTGTTAATACAAAAACAGTAAATTTGAAGACTGAGAACCATATAAGAGGGTGATTGCACTTATTATGAAAAGATTTGAATCCTTCTTTGTGTGTGTGGGTGTGACCAGCCTTGCTATCAATTTCTTCTGTCATACACTGCCAAATTTTCTATTTAAGTATTGTGAAAACTCTGTTTTTTTCAGGTCGAATGAGTGATTTGAGTGTAATTGGTCATCCAATAGATTCAGAATCTAAAGAAGATGAACCTTGTAGTGAAGAAACAGATCCAGTGCATGATCTAATGGCTGAAATTTTACCTGAATTCCCTGACATAATTGAAATAGACCTATACCACAGTGAAGAAAATGAAGAAGAAGAAGAAGAGTGTGCAAATGCTACTGATGTGACAACCACCCCATCTGTGCAGTACATAAATGGGAAGCATCTCGTTACCACTGTGCCCAAGGACCCAGAAGCTGCAGAAGCTAGGCGTGGCCAGTTTGAAAGTGTTGCACCTTCTCAGAATTTCTCGGACAGCTCTGAAAGTGATACTCATCCATTTGTAATAGCCAAAACGGAATTGTCTACTGCTGTGCAACCTAATGAATCTACAGAAACAACTGAGTCTCTTGAAGTTACATGGAAGCCTGAGACTTACC-T is Pathogenic according to our data. Variant chr5-83536654-TCTTAATTTTACTCTTTTTGCAGTTCACACAAAGATGAATTCCTGCACTTCAAGATTACATTGTATATGTGATTCCTTGCTTCATTTTAAGGACTATGTTGTTTTCTTAAATGTGTTGATGAGTCTTTATAACCTGTTTTAATAATGTTAAATTGAATTCATTTTTCTTATTGTTAATACAAAAACAGTAAATTTGAAGACTGAGAACCATATAAGAGGGTGATTGCACTTATTATGAAAAGATTTGAATCCTTCTTTGTGTGTGTGGGTGTGACCAGCCTTGCTATCAATTTCTTCTGTCATACACTGCCAAATTTTCTATTTAAGTATTGTGAAAACTCTGTTTTTTTCAGGTCGAATGAGTGATTTGAGTGTAATTGGTCATCCAATAGATTCAGAATCTAAAGAAGATGAACCTTGTAGTGAAGAAACAGATCCAGTGCATGATCTAATGGCTGAAATTTTACCTGAATTCCCTGACATAATTGAAATAGACCTATACCACAGTGAAGAAAATGAAGAAGAAGAAGAAGAGTGTGCAAATGCTACTGATGTGACAACCACCCCATCTGTGCAGTACATAAATGGGAAGCATCTCGTTACCACTGTGCCCAAGGACCCAGAAGCTGCAGAAGCTAGGCGTGGCCAGTTTGAAAGTGTTGCACCTTCTCAGAATTTCTCGGACAGCTCTGAAAGTGATACTCATCCATTTGTAATAGCCAAAACGGAATTGTCTACTGCTGTGCAACCTAATGAATCTACAGAAACAACTGAGTCTCTTGAAGTTACATGGAAGCCTGAGACTTACC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2024338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCAN	NM_004385.5	c.4004-350_4461del	p.Arg1336fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 8 of 15	ENST00000265077.8	NP_004376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCAN	ENST00000265077.8	c.4004-350_4461del	p.Arg1336fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 8 of 15	1	NM_004385.5	ENSP00000265077.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 8 (c.4004-350_4461del) of the VCAN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in VCAN are known to be pathogenic (PMID: 26720455). This variant has not been reported in the literature in individuals affected with VCAN-related conditions. ClinVar contains an entry for this variant (Variation ID: 2024338). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-82832473;