rs121913568

Variant names:

• chr15-88872038-G-A
• rs121913568
• NM_001369268.1:c.7255G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-88872038-G-A
• chr15-88872038-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.89
• Publications: 4 publications found

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]

ACAN Gene-Disease associations (from GenCC):

• osteochondritis dissecans

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• spondyloepiphyseal dysplasia, Kimberley type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spondyloepimetaphyseal dysplasia, aggrecan type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• short stature-advanced bone age-early-onset osteoarthritis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 14305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.7255G>A	p.Asp2419Asn	missense_variant	Exon 16 of 19	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.7255G>A	p.Asp2419Asn	missense_variant	Exon 16 of 19	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans Pathogenic:2

Mar 29, 2024

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondyloepimetaphyseal dysplasia, aggrecan type Pathogenic:1

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This variant is not present in population databases (gnomAD no frequency). 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 also known as c.6799G>A (p.D2267N). ClinVar contains an entry for this variant (Variation ID: 14305). 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"). Experimental studies have shown that this missense change affects ACAN function (PMID: 19110214). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
PhyloP100		9.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	.;D;.;D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	.;D;.;D;D;D
Sift4G	Pathogenic	0.0	.;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		1.0	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.91
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs121913568; hg19: chr15-89415269;