rs121913568
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001369268.1(ACAN):c.7255G>A(p.Asp2419Asn) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ACAN
NM_001369268.1 missense
NM_001369268.1 missense
Scores
9
3
5
Clinical Significance
Conservation
PhyloP100: 9.89
Genes affected
ACAN (HGNC:319): (aggrecan) This gene is a member of the aggrecan/versican proteoglycan family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage. Mutations in this gene may be involved in skeletal dysplasia and spinal degeneration. Multiple alternatively spliced transcript variants that encode different protein isoforms have been observed in this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909
PP5
Variant 15-88872038-G-A is Pathogenic according to our data. Variant chr15-88872038-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACAN | NM_001369268.1 | c.7255G>A | p.Asp2419Asn | missense_variant | 16/19 | ENST00000560601.4 | NP_001356197.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACAN | ENST00000560601.4 | c.7255G>A | p.Asp2419Asn | missense_variant | 16/19 | 3 | NM_001369268.1 | ENSP00000453581 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Mar 29, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Spondyloepimetaphyseal dysplasia, aggrecan type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2022 | 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. Experimental studies have shown that this missense change affects ACAN function (PMID: 19110214). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 14305). This variant is also known as c.6799G>A (p.D2267N). This missense change has been observed in individual(s) with autosomal recessive spondyloepimetaphyseal dysplasia (PMID: 19110214). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2381 of the ACAN protein (p.Asp2381Asn). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;D;D;D
REVEL
Uncertain
Sift
Pathogenic
.;D;.;D;D;D
Sift4G
Pathogenic
.;D;D;D;D;D
Vest4
0.77, 0.66, 0.84, 0.89
MutPred
0.87
.;Loss of phosphorylation at T2383 (P = 0.1046);.;.;.;Loss of phosphorylation at T2383 (P = 0.1046);
MVP
0.84
MPC
0.76
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at