15-88874398-G-A

Variant names:

• chr15-88874398-G-A
• rs2280465
• NM_001369268.1:c.7631-7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369268.1(ACAN):​c.7631-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,595,604 control chromosomes in the GnomAD database, including 38,239 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3219 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35020 hom.)
• Consequence: ACAN NM_001369268.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001136
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -6.04
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-88874398-G-A is Benign according to our data. Variant chr15-88874398-G-A is described in ClinVar as Benign. ClinVar VariationId is 1188850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	NM_001369268.1	MANE Select	c.7631-7G>A		splice_region intron	N/A	NP_001356197.1
	ACAN	NM_001411097.1		c.7517-7G>A		splice_region intron	N/A	NP_001398026.1
	ACAN	NM_013227.4		c.7517-7G>A		splice_region intron	N/A	NP_037359.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	ENST00000560601.4	TSL:3 MANE Select	c.7631-7G>A		splice_region intron	N/A	ENSP00000453581.2
	ACAN	ENST00000439576.7	TSL:5	c.7517-7G>A		splice_region intron	N/A	ENSP00000387356.2
	ACAN	ENST00000561243.7	TSL:5	c.7517-7G>A		splice_region intron	N/A	ENSP00000453342.3

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30753 AN: 151700 Hom.: 3209 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.201 AC: 44585 AN: 222244 AF XY: 0.204

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.0934

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.218 AC: 314693 AN: 1443786 Hom.: 35020 Cov.: 32 AF XY: 0.218 AC XY: 156455 AN XY: 716686

African (AFR) AF: 0.180 AC: 5937 AN: 33034

American (AMR) AF: 0.192 AC: 8119 AN: 42326

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 6936 AN: 25792

East Asian (EAS) AF: 0.0858 AC: 3337 AN: 38912

South Asian (SAS) AF: 0.214 AC: 17774 AN: 83178

European-Finnish (FIN) AF: 0.162 AC: 8466 AN: 52258

Middle Eastern (MID) AF: 0.281 AC: 1598 AN: 5692

European-Non Finnish (NFE) AF: 0.226 AC: 249346 AN: 1102876

Other (OTH) AF: 0.221 AC: 13180 AN: 59718

GnomAD4 genome AF: 0.203 AC: 30778 AN: 151818 Hom.: 3219 Cov.: 32 AF XY: 0.202 AC XY: 15017 AN XY: 74192

African (AFR) AF: 0.177 AC: 7311 AN: 41396

American (AMR) AF: 0.213 AC: 3254 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 953 AN: 3466

East Asian (EAS) AF: 0.102 AC: 524 AN: 5130

South Asian (SAS) AF: 0.199 AC: 954 AN: 4790

European-Finnish (FIN) AF: 0.159 AC: 1681 AN: 10558

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15248 AN: 67916

Other (OTH) AF: 0.218 AC: 460 AN: 2110

Alfa AF: 0.220 Hom.: 4823

Bravo AF: 0.206

Asia WGS AF: 0.189 AC: 657 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Osteochondritis dissecans Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spondyloepiphyseal dysplasia, Kimberley type Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.15
DANN	Benign	0.92
PhyloP100		-6.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.030		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: rs2280465; hg19: chr15-89417629;