rs2280465

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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

ACAN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1 link	c.7631-7G>A		splice_region_variant, intron_variant	Intron 18 of 18	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4 link	c.7631-7G>A		splice_region_variant, intron_variant	Intron 18 of 18	3	NM_001369268.1	ENSP00000453581.2		H0YMF1

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30753

AN:

151700

Hom.:

3209

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.218

AC XY:

156455

AN XY:

716686

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

12395

24790

37185

49580

61975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8584

17168

25752

34336

42920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.203

AC:

30778

AN:

151818

Hom.:

3219

Cov.:

AF XY:

0.202

AC XY:

15017

AN XY:

74192

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.225

AC:

15248

AN:

67916

Other (OTH)

AF:

0.218

AC:

460

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1253

2506

3760

5013

6266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.15

(source)

DANN

Benign

0.92

PhyloP100

-6.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over