15-88812680-C-T

Variant names:

• chr15-88812680-C-T
• rs12439075
• NM_001369268.1:c.-8+8871C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001369268.1(ACAN):​c.-8+8871C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 151,626 control chromosomes in the GnomAD database, including 8,872 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8872 hom., cov: 32)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.-8+8871C>T		intron_variant	Intron 1 of 18	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.-8+8871C>T		intron_variant	Intron 1 of 18	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49257 AN: 151514 Hom.: 8854 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.325 AC: 49304 AN: 151626 Hom.: 8872 Cov.: 32 AF XY: 0.337 AC XY: 24989 AN XY: 74052

African (AFR) AF: 0.190 AC: 7886 AN: 41432

American (AMR) AF: 0.419 AC: 6376 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 886 AN: 3464

East Asian (EAS) AF: 0.595 AC: 3063 AN: 5146

South Asian (SAS) AF: 0.421 AC: 2024 AN: 4804

European-Finnish (FIN) AF: 0.478 AC: 4954 AN: 10354

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.339 AC: 23005 AN: 67882

Other (OTH) AF: 0.322 AC: 679 AN: 2108

Alfa AF: 0.329 Hom.: 28416

Bravo AF: 0.316

Asia WGS AF: 0.490 AC: 1705 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.61
DANN	Benign	0.34
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs12439075; hg19: chr15-89355911;