rs9630453

Variant names:

• chr15-88860691-A-G
• rs9630453
• NM_001369268.1:c.6946+252A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001369268.1(ACAN):​c.6946+252A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 152,204 control chromosomes in the GnomAD database, including 8,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (8937 hom., cov: 32)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.388
• Publications: 7 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-88860691-A-G is Benign according to our data. Variant chr15-88860691-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

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.6946+252A>G		intron	N/A	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.6832+1274A>G		intron	N/A	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.6946+252A>G		intron	N/A	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.6946+252A>G		intron	N/A	ENSP00000453581.2	P16112-4
	ACAN	ENST00000439576.7	TSL:5	c.6946+252A>G		intron	N/A	ENSP00000387356.2	P16112-1
	ACAN	ENST00000561243.7	TSL:5	c.6832+1274A>G		intron	N/A	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37158 AN: 152086 Hom.: 8893 Cov.: 32

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0646

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.0554

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.209

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

GnomAD4 genome AF: 0.245 AC: 37252 AN: 152204 Hom.: 8937 Cov.: 32 AF XY: 0.242 AC XY: 18028 AN XY: 74422

African (AFR) AF: 0.624 AC: 25899 AN: 41478

American (AMR) AF: 0.141 AC: 2164 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3468

East Asian (EAS) AF: 0.0648 AC: 336 AN: 5186

South Asian (SAS) AF: 0.281 AC: 1353 AN: 4822

European-Finnish (FIN) AF: 0.0554 AC: 588 AN: 10618

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0874 AC: 5942 AN: 68012

Other (OTH) AF: 0.206 AC: 436 AN: 2112

Alfa AF: 0.151 Hom.: 8836

Bravo AF: 0.265

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.39
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9630453; hg19: chr15-89403922;