rs2280465

chr15-88874398-G-Achr15-88874398-G-T

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001136
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.04

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1188850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88874398-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAN	NM_001369268.1	c.7631-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000560601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAN	ENST00000560601.4	c.7631-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3	NM_001369268.1	P1

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

GnomAD3 exomes AF: 0.201 AC: 44585 AN: 222244 Hom.: 4542 AF XY: 0.204 AC XY: 24568 AN XY: 120472

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 SAS exome AF: 0.212

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

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.0858

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.221

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

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.218

Alfa AF: 0.221 Hom.: 3699

Bravo AF: 0.206

Asia WGS AF: 0.189 AC: 657 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Osteochondritis dissecans Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Spondyloepiphyseal dysplasia, Kimberley type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.15
Dann	Benign	0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs2280465; hg19: chr15-89417629;