dbSNP rs1042631: ACAN:p.Leu2141Leu (chr15-88859008-T-C) – ACMG Classification: Benign (-21 pts)

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.6423T>C(p.Leu2141Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,613,796 control chromosomes in the GnomAD database, including 486,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 47112 hom., cov: 32)

Exomes 𝑓: 0.77 ( 439201 hom. )

Consequence

ACAN
NM_001369268.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.81

Publications

32 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):

ACAN-related short stature spectrum
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
osteochondritis dissecans
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
spondyloepimetaphyseal dysplasia, aggrecan type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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=-1.03).

BP6

Variant 15-88859008-T-C is Benign according to our data. Variant chr15-88859008-T-C is described in ClinVar as Benign. ClinVar VariationId is 1188994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 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	UniProt
ACAN	NM_001369268.1	MANE Select	c.6423T>C	p.Leu2141Leu	synonymous	Exon 12 of 19	NP_001356197.1	P16112-4
ACAN	NM_001411097.1		c.6423T>C	p.Leu2141Leu	synonymous	Exon 12 of 18	NP_001398026.1	A0A5K1VW97
ACAN	NM_013227.4		c.6423T>C	p.Leu2141Leu	synonymous	Exon 12 of 18	NP_037359.3	P16112-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACAN	ENST00000560601.4	TSL:3 MANE Select	c.6423T>C	p.Leu2141Leu	synonymous	Exon 12 of 19	ENSP00000453581.2	P16112-4
ACAN	ENST00000439576.7	TSL:5	c.6423T>C	p.Leu2141Leu	synonymous	Exon 12 of 18	ENSP00000387356.2	P16112-1
ACAN	ENST00000561243.7	TSL:5	c.6423T>C	p.Leu2141Leu	synonymous	Exon 12 of 18	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes

AF:

0.785

AC:

119292

AN:

152052

Hom.:

47083

Cov.:

show subpopulations

Gnomad AFR

AF:

0.849

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.700

Gnomad ASJ

AF:

0.786

Gnomad EAS

AF:

0.590

Gnomad SAS

AF:

0.693

Gnomad FIN

AF:

0.717

Gnomad MID

AF:

0.763

Gnomad NFE

AF:

0.797

Gnomad OTH

AF:

0.785

GnomAD2 exomes

AF:

0.730

AC:

181887

AN:

249080

AF XY:

0.733

show subpopulations

Gnomad AFR exome

AF:

0.851

Gnomad AMR exome

AF:

0.574

Gnomad ASJ exome

AF:

0.787

Gnomad EAS exome

AF:

0.586

Gnomad FIN exome

AF:

0.713

Gnomad NFE exome

AF:

0.795

Gnomad OTH exome

AF:

0.750

GnomAD4 exome

AF:

0.772

AC:

1128855

AN:

1461626

Hom.:

439201

Cov.:

AF XY:

0.770

AC XY:

559774

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.848

AC:

28391

AN:

33480

American (AMR)

AF:

0.590

AC:

26379

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.785

AC:

20523

AN:

26136

East Asian (EAS)

AF:

0.537

AC:

21327

AN:

39700

South Asian (SAS)

AF:

0.682

AC:

58833

AN:

86258

European-Finnish (FIN)

AF:

0.710

AC:

37835

AN:

53324

Middle Eastern (MID)

AF:

0.767

AC:

4424

AN:

5768

European-Non Finnish (NFE)

AF:

0.796

AC:

884761

AN:

1111862

Other (OTH)

AF:

0.768

AC:

46382

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

17210

34420

51631

68841

86051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20666

41332

61998

82664

103330

<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:

0.784

AC:

119371

AN:

152170

Hom.:

47112

Cov.:

AF XY:

0.774

AC XY:

57600

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.848

AC:

35227

AN:

41520

American (AMR)

AF:

0.699

AC:

10689

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.786

AC:

2726

AN:

3470

East Asian (EAS)

AF:

0.590

AC:

3037

AN:

5150

South Asian (SAS)

AF:

0.694

AC:

3343

AN:

4814

European-Finnish (FIN)

AF:

0.717

AC:

7604

AN:

10602

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.797

AC:

54227

AN:

68000

Other (OTH)

AF:

0.782

AC:

1654

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1306

2612

3918

5224

6530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

868

1736

2604

3472

4340

<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:

0.787

Hom.:

179268

Bravo

AF:

0.782

Asia WGS

AF:

0.676

AC:

2352

AN:

3478

EpiCase

AF:

0.794

EpiControl

AF:

0.800

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

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

-1.0

CADD

Benign

0.11

(source)

DANN

Benign

0.28

PhyloP100

-1.8

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.

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

Computational scores

Splicing

Publications

Other links and lift over