15-88857108-A-C

Variant names:

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.4523A>C(p.Glu1508Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 1,612,950 control chromosomes in the GnomAD database, including 297,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 22314 hom., cov: 31)

Exomes 𝑓: 0.60 ( 275047 hom. )

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.28

Publications

43 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 (MetaRNN=6.0151356E-6).

BP6

Variant 15-88857108-A-C is Benign according to our data. Variant chr15-88857108-A-C is described in ClinVar as Benign. ClinVar VariationId is 283836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.64 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACAN	NM_001369268.1	MANE Select	c.4523A>C	p.Glu1508Ala	missense	Exon 12 of 19	NP_001356197.1
ACAN	NM_001411097.1		c.4523A>C	p.Glu1508Ala	missense	Exon 12 of 18	NP_001398026.1
ACAN	NM_013227.4		c.4523A>C	p.Glu1508Ala	missense	Exon 12 of 18	NP_037359.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACAN	ENST00000560601.4	TSL:3 MANE Select	c.4523A>C	p.Glu1508Ala	missense	Exon 12 of 19	ENSP00000453581.2
ACAN	ENST00000439576.7	TSL:5	c.4523A>C	p.Glu1508Ala	missense	Exon 12 of 18	ENSP00000387356.2
ACAN	ENST00000561243.7	TSL:5	c.4523A>C	p.Glu1508Ala	missense	Exon 12 of 18	ENSP00000453342.3

Frequencies

GnomAD3 genomes

AF:

0.529

AC:

80012

AN:

151262

Hom.:

22317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.658

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.599

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.516

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.561

Gnomad NFE

AF:

0.645

Gnomad OTH

AF:

0.553

GnomAD2 exomes

AF:

0.525

AC:

130849

AN:

249176

AF XY:

0.538

show subpopulations

Gnomad AFR exome

AF:

0.366

Gnomad AMR exome

AF:

0.316

Gnomad ASJ exome

AF:

0.606

Gnomad EAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.588

Gnomad NFE exome

AF:

0.644

Gnomad OTH exome

AF:

0.567

GnomAD4 exome

AF:

0.605

AC:

883519

AN:

1461570

Hom.:

275047

Cov.:

AF XY:

0.604

AC XY:

438969

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.367

AC:

12294

AN:

33480

American (AMR)

AF:

0.330

AC:

14752

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.604

AC:

15775

AN:

26136

East Asian (EAS)

AF:

0.216

AC:

8567

AN:

39698

South Asian (SAS)

AF:

0.505

AC:

43574

AN:

86248

European-Finnish (FIN)

AF:

0.587

AC:

31299

AN:

53348

Middle Eastern (MID)

AF:

0.588

AC:

3394

AN:

5768

European-Non Finnish (NFE)

AF:

0.647

AC:

719001

AN:

1111802

Other (OTH)

AF:

0.577

AC:

34863

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

22576

45152

67728

90304

112880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18592

37184

55776

74368

92960

<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:

0.529

AC:

80019

AN:

151380

Hom.:

22314

Cov.:

AF XY:

0.521

AC XY:

38560

AN XY:

73960

show subpopulations

African (AFR)

AF:

0.377

AC:

15496

AN:

41148

American (AMR)

AF:

0.445

AC:

6776

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

2079

AN:

3472

East Asian (EAS)

AF:

0.233

AC:

1180

AN:

5068

South Asian (SAS)

AF:

0.516

AC:

2472

AN:

4790

European-Finnish (FIN)

AF:

0.599

AC:

6305

AN:

10532

Middle Eastern (MID)

AF:

0.566

AC:

164

AN:

290

European-Non Finnish (NFE)

AF:

0.645

AC:

43791

AN:

67856

Other (OTH)

AF:

0.552

AC:

1157

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1817

3634

5451

7268

9085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.591

Hom.:

71396

Bravo

AF:

0.505

TwinsUK

AF:

0.665

AC:

2464

ALSPAC

AF:

0.655

AC:

2523

ESP6500AA

AF:

0.393

AC:

1469

ESP6500EA

AF:

0.649

AC:

5322

ExAC

AF:

0.534

AC:

64560

Asia WGS

AF:

0.412

AC:

1432

AN:

3478

EpiCase

AF:

0.640

EpiControl

AF:

0.642

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17317784)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Nov 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.27

CADD

Benign

6.7

(source)

DANN

Benign

0.68

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0000060

MetaSVM

Benign

-0.99

PhyloP100

1.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.54

REVEL

Benign

0.19

Sift

Uncertain

0.014

Sift4G

Benign

0.76

Vest4

0.045

MPC

0.26

ClinPred

0.0047

GERP RS

-2.1

Varity_R

0.039

gMVP

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over