rs8042988

Variant names:

• chr15-88869048-A-G
• rs8042988
• NM_001369268.1:c.7060+719A>G

Variant summary

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

The NM_001369268.1(ACAN):​c.7060+719A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,992 control chromosomes in the GnomAD database, including 15,427 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 0.43 (15427 hom., cov: 32)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.278
• 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):

• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.7060+719A>G		intron_variant	Intron 14 of 18	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.7060+719A>G		intron_variant	Intron 14 of 18	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64717 AN: 151874 Hom.: 15379 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.404

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

GnomAD4 genome AF: 0.426 AC: 64819 AN: 151992 Hom.: 15427 Cov.: 32 AF XY: 0.423 AC XY: 31452 AN XY: 74276

African (AFR) AF: 0.664 AC: 27519 AN: 41464

American (AMR) AF: 0.323 AC: 4932 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3468

East Asian (EAS) AF: 0.305 AC: 1573 AN: 5156

South Asian (SAS) AF: 0.343 AC: 1654 AN: 4818

European-Finnish (FIN) AF: 0.352 AC: 3718 AN: 10558

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.340 AC: 23082 AN: 67930

Other (OTH) AF: 0.405 AC: 855 AN: 2112

Alfa AF: 0.363 Hom.: 43132

Bravo AF: 0.432

Asia WGS AF: 0.331 AC: 1150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.30
DANN	Benign	0.51
PhyloP100		-0.28
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: rs8042988; hg19: chr15-89412279;