NM_001369268.1:c.2815T>A

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.2815T>A(p.Ser939Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,116 control chromosomes in the GnomAD database, including 291,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21853 hom., cov: 33)

Exomes 𝑓: 0.60 ( 269706 hom. )

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.123

Publications

33 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=8.623954E-6).

BP6

Variant 15-88855400-T-A is Benign according to our data. Variant chr15-88855400-T-A is described in ClinVar as Benign. ClinVar VariationId is 1174760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1 link	c.2815T>A	p.Ser939Thr	missense_variant	Exon 12 of 19	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4 link	c.2815T>A	p.Ser939Thr	missense_variant	Exon 12 of 19	3	NM_001369268.1	ENSP00000453581.2		H0YMF1

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

78961

AN:

151748

Hom.:

21858

Cov.:

show subpopulations

Gnomad AFR

AF:

0.372

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.443

Gnomad ASJ

AF:

0.595

Gnomad EAS

AF:

0.194

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.595

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.643

Gnomad OTH

AF:

0.547

GnomAD2 exomes

AF:

0.508

AC:

126518

AN:

248810

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.604

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.588

Gnomad NFE exome

AF:

0.642

Gnomad OTH exome

AF:

0.555

GnomAD4 exome

AF:

0.597

AC:

871672

AN:

1461250

Hom.:

269706

Cov.:

AF XY:

0.593

AC XY:

431103

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.366

AC:

12239

AN:

33472

American (AMR)

AF:

0.329

AC:

14692

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.602

AC:

15733

AN:

26124

East Asian (EAS)

AF:

0.192

AC:

7622

AN:

39696

South Asian (SAS)

AF:

0.404

AC:

34875

AN:

86238

European-Finnish (FIN)

AF:

0.586

AC:

31195

AN:

53198

Middle Eastern (MID)

AF:

0.582

AC:

3353

AN:

5764

European-Non Finnish (NFE)

AF:

0.646

AC:

717866

AN:

1111690

Other (OTH)

AF:

0.565

AC:

34097

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

23515

47030

70546

94061

117576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18520

37040

55560

74080

92600

<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:

0.520

AC:

78961

AN:

151866

Hom.:

21853

Cov.:

AF XY:

0.511

AC XY:

37924

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.372

AC:

15407

AN:

41446

American (AMR)

AF:

0.441

AC:

6746

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.595

AC:

2060

AN:

3462

East Asian (EAS)

AF:

0.195

AC:

1007

AN:

5172

South Asian (SAS)

AF:

0.402

AC:

1933

AN:

4808

European-Finnish (FIN)

AF:

0.595

AC:

6259

AN:

10526

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.643

AC:

43634

AN:

67858

Other (OTH)

AF:

0.547

AC:

1154

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1887

3775

5662

7550

9437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.606

Hom.:

9228

Bravo

AF:

0.502

TwinsUK

AF:

0.664

AC:

2462

ALSPAC

AF:

0.654

AC:

2519

ESP6500AA

AF:

0.392

AC:

1491

ESP6500EA

AF:

0.648

AC:

5335

ExAC

AF:

0.517

AC:

62405

Asia WGS

AF:

0.337

AC:

1173

AN:

3478

EpiCase

AF:

0.638

EpiControl

AF:

0.640

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

Benign:1

Dec 05, 2021

Genome-Nilou Lab

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.1

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.55

T;T;T;T;T;.

MetaRNN

Benign

0.0000086

T;T;T;T;T;T

MetaSVM

Benign

-0.93

PhyloP100

-0.12

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

.;N;.;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.14

.;T;.;T;T;T

Sift4G

Uncertain

0.025

.;D;T;T;D;D

Vest4

0.054, 0.067, 0.049, 0.052, 0.030

MPC

0.27

ClinPred

0.0044

GERP RS

1.2

Varity_R

0.096

gMVP

0.24

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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