Genetic Variant NM_001369268.1:c.2289C>T (chr15-88854874-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001369268.1(ACAN):c.2289C>T(p.Pro763Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,494,474 control chromosomes in the GnomAD database, including 270,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 20173 hom., cov: 33)

Exomes 𝑓: 0.60 ( 250780 hom. )

Consequence

ACAN
NM_001369268.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.817

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):

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 15-88854874-C-T is Benign according to our data. Variant chr15-88854874-C-T is described in ClinVar as Benign. ClinVar VariationId is 1181962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.817 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.638 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.2289C>T	p.Pro763Pro	synonymous	Exon 12 of 19	NP_001356197.1	P16112-4
ACAN	NM_001411097.1		c.2289C>T	p.Pro763Pro	synonymous	Exon 12 of 18	NP_001398026.1	A0A5K1VW97
ACAN	NM_013227.4		c.2289C>T	p.Pro763Pro	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.2289C>T	p.Pro763Pro	synonymous	Exon 12 of 19	ENSP00000453581.2	P16112-4
ACAN	ENST00000439576.7	TSL:5	c.2289C>T	p.Pro763Pro	synonymous	Exon 12 of 18	ENSP00000387356.2	P16112-1
ACAN	ENST00000561243.7	TSL:5	c.2289C>T	p.Pro763Pro	synonymous	Exon 12 of 18	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73335

AN:

151986

Hom.:

20175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.659

Gnomad AMR

AF:

0.429

Gnomad ASJ

AF:

0.596

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.596

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.643

Gnomad OTH

AF:

0.519

GnomAD2 exomes

AF:

0.504

AC:

80915

AN:

160402

AF XY:

0.519

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.313

Gnomad ASJ exome

AF:

0.614

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.591

Gnomad NFE exome

AF:

0.640

Gnomad OTH exome

AF:

0.546

GnomAD4 exome

AF:

0.600

AC:

805043

AN:

1342370

Hom.:

250780

Cov.:

AF XY:

0.597

AC XY:

392611

AN XY:

657470

show subpopulations

African (AFR)

AF:

0.224

AC:

6632

AN:

29544

American (AMR)

AF:

0.333

AC:

8742

AN:

26230

Ashkenazi Jewish (ASJ)

AF:

0.603

AC:

12290

AN:

20394

East Asian (EAS)

AF:

0.192

AC:

7154

AN:

37246

South Asian (SAS)

AF:

0.405

AC:

25510

AN:

63002

European-Finnish (FIN)

AF:

0.587

AC:

28987

AN:

49384

Middle Eastern (MID)

AF:

0.573

AC:

3051

AN:

5320

European-Non Finnish (NFE)

AF:

0.646

AC:

681915

AN:

1056066

Other (OTH)

AF:

0.557

AC:

30762

AN:

55184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

16059

32118

48177

64236

80295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18304

36608

54912

73216

91520

<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:

0.482

AC:

73330

AN:

152104

Hom.:

20173

Cov.:

AF XY:

0.475

AC XY:

35305

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.238

AC:

9877

AN:

41472

American (AMR)

AF:

0.428

AC:

6540

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

2070

AN:

3472

East Asian (EAS)

AF:

0.194

AC:

1001

AN:

5166

South Asian (SAS)

AF:

0.402

AC:

1935

AN:

4818

European-Finnish (FIN)

AF:

0.596

AC:

6309

AN:

10580

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.643

AC:

43736

AN:

67980

Other (OTH)

AF:

0.519

AC:

1097

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1736

3472

5207

6943

8679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

644

1288

1932

2576

3220

<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:

0.583

Hom.:

98831

Bravo

AF:

0.457

Asia WGS

AF:

0.333

AC:

1158

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

-0.41

CADD

Benign

9.5

(source)

DANN

Benign

0.44

PhyloP100

0.82

Mutation Taster

=99/1

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