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:5
• 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):

• ACAN-related short stature spectrum

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• osteochondritis dissecans

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369268.1. 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
	ACAN	NM_001369268.1	MANE Select	c.7255G>A	p.Asp2419Asn	missense	Exon 16 of 19	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.7141G>A	p.Asp2381Asn	missense	Exon 15 of 18	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.7141G>A	p.Asp2381Asn	missense	Exon 15 of 18	NP_037359.3	P16112-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	ENST00000560601.4	TSL:3 MANE Select	c.7255G>A	p.Asp2419Asn	missense	Exon 16 of 19	ENSP00000453581.2	P16112-4
	ACAN	ENST00000439576.7	TSL:5	c.7141G>A	p.Asp2381Asn	missense	Exon 15 of 18	ENSP00000387356.2	P16112-1
	ACAN	ENST00000561243.7	TSL:5	c.7141G>A	p.Asp2381Asn	missense	Exon 15 of 18	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (2)
2	-	-	Spondyloepimetaphyseal dysplasia, aggrecan type (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.76	T
PhyloP100		9.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.77
MutPred		0.87		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;