5-83536654-TCTTAATTTTACTCTTTTTGCAGTTCACACAAAGATGAATTCCTGCACTTCAAGATTACATTGTATATGTGATTCCTTGCTTCATTTTAAGGACTATGTTGTTTTCTTAAATGTGTTGATGAGTCTTTATAACCTGTTTTAATAATGTTAAATTGAATTCATTTTTCTTATTGTTAATACAAAAACAGTAAATTTGAAGACTGAGAACCATATAAGAGGGTGATTGCACTTATTATGAAAAGATTTGAATCCTTCTTTGTGTGTGTGGGTGTGACCAGCCTTGCTATCAATTTCTTCTGTCATACACTGCCAAATTTTCTATTTAAGTATTGTGAAAACTCTGTTTTTTTCAGGTCGAATGAGTGATTTGAGTGTAATTGGTCATCCAATAGATTCAGAATCTAAAGAAGATGAACCTTGTAGTGAAGAAACAGATCCAGTGCATGATCTAATGGCTGAAATTTTACCTGAATTCCCTGACATAATTGAAATAGACCTATACCACAGTGAAGAAAATGAAGAAGAAGAAGAAGAGTGTGCAAATGCTACTGATGTGACAACCACCCCATCTGTGCAGTACATAAATGGGAAGCATCTCGTTACCACTGTGCCCAAGGACCCAGAAGCTGCAGAAGCTAGGCGTGGCCAGTTTGAAAGTGTTGCACCTTCTCAGAATTTCTCGGACAGCTCTGAAAGTGATACTCATCCATTTGTAATAGCCAAAACGGAATTGTCTACTGCTGTGCAACCTAATGAATCTACAGAAACAACTGAGTCTCTTGAAGTTACATGGAAGCCTGAGACTTACC-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 2024338.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004385.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	NM_004385.5	MANE Select	c.4004-350_4461del	p.Arg1336fs	frameshift splice_acceptor splice_region intron	Exon 8 of 15	NP_004376.2
	VCAN	NM_001164097.2		c.1043-350_1500del	p.Arg349fs	frameshift splice_acceptor splice_region intron	Exon 7 of 14	NP_001157569.1	P13611-2
	VCAN	NM_001164098.2		c.4004-8880_4004-8073del		intron	N/A	NP_001157570.1	P13611-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCAN	ENST00000265077.8	TSL:1 MANE Select	c.4004-350_4461del	p.Arg1336fs	frameshift splice_acceptor splice_region intron	Exon 8 of 15	ENSP00000265077.3	P13611-1
	VCAN	ENST00000343200.9	TSL:1	c.1043-350_1500del	p.Arg349fs	frameshift splice_acceptor splice_region intron	Exon 7 of 14	ENSP00000340062.5	P13611-2
	VCAN	ENST00000342785.8	TSL:1	c.4004-8880_4004-8073del		intron	N/A	ENSP00000342768.4	P13611-3

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

Splicing

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

Other links and lift over

hg19: chr5-82832473;