Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001369268.1(ACAN):c.1221C>T(p.Val407Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,614,024 control chromosomes in the GnomAD database, including 1,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V407V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.062 ( 512 hom., cov: 33)

Exomes 𝑓: 0.033 ( 1346 hom. )

Consequence

ACAN
NM_001369268.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.745

Publications

47 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 15-88845674-C-T is Benign according to our data. Variant chr15-88845674-C-T is described in ClinVar as Benign. ClinVar VariationId is 1206376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.745 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 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.1221C>T	p.Val407Val	synonymous	Exon 7 of 19	NP_001356197.1
ACAN	NM_001411097.1		c.1221C>T	p.Val407Val	synonymous	Exon 7 of 18	NP_001398026.1
ACAN	NM_013227.4		c.1221C>T	p.Val407Val	synonymous	Exon 7 of 18	NP_037359.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACAN	ENST00000560601.4	TSL:3 MANE Select	c.1221C>T	p.Val407Val	synonymous	Exon 7 of 19	ENSP00000453581.2
ACAN	ENST00000558207.5	TSL:1	c.1221C>T	p.Val407Val	synonymous	Exon 7 of 10	ENSP00000453003.1
ACAN	ENST00000439576.7	TSL:5	c.1221C>T	p.Val407Val	synonymous	Exon 7 of 18	ENSP00000387356.2

Frequencies

GnomAD3 genomes

AF:

0.0619

AC:

9428

AN:

152216

Hom.:

511

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0438

Gnomad ASJ

AF:

0.0504

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0575

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0267

Gnomad OTH

AF:

0.0598

GnomAD2 exomes

AF:

0.0376

AC:

9344

AN:

248452

AF XY:

0.0379

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.0252

Gnomad ASJ exome

AF:

0.0511

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.0293

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

AF:

0.0334

AC:

48871

AN:

1461690

Hom.:

1346

Cov.:

AF XY:

0.0341

AC XY:

24795

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.149

AC:

5005

AN:

33480

American (AMR)

AF:

0.0274

AC:

1225

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0497

AC:

1298

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0618

AC:

5334

AN:

86258

European-Finnish (FIN)

AF:

0.0145

AC:

772

AN:

53390

Middle Eastern (MID)

AF:

0.0856

AC:

494

AN:

5768

European-Non Finnish (NFE)

AF:

0.0289

AC:

32186

AN:

1111862

Other (OTH)

AF:

0.0423

AC:

2553

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3009

6017

9026

12034

15043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1304

2608

3912

5216

6520

<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:

0.0619

AC:

9429

AN:

152334

Hom.:

512

Cov.:

AF XY:

0.0623

AC XY:

4639

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.148

AC:

6150

AN:

41564

American (AMR)

AF:

0.0438

AC:

670

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0504

AC:

175

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0565

AC:

273

AN:

4830

European-Finnish (FIN)

AF:

0.0148

AC:

157

AN:

10628

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0267

AC:

1817

AN:

68028

Other (OTH)

AF:

0.0592

AC:

125

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

450

900

1350

1800

2250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0375

Hom.:

766

Bravo

AF:

0.0676

Asia WGS

AF:

0.0360

AC:

127

AN:

3478

EpiCase

AF:

0.0321

EpiControl

AF:

0.0345

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (1)

Spondyloepimetaphyseal dysplasia, aggrecan type (1)

Spondyloepiphyseal dysplasia, Kimberley type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.1

(source)

DANN

Benign

0.32

PhyloP100

0.74

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

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

rs16942341

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over