rs150555123

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001369268.1(ACAN):c.7189G>A(p.Val2397Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,546 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2397L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.206

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104419334

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019824654).

BP6

Variant 15-88871510-G-A is Benign according to our data. Variant chr15-88871510-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445914.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00088 (134/152328) while in subpopulation AMR AF = 0.00196 (30/15300). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.7189G>A	p.Val2397Ile	missense	Exon 15 of 19	NP_001356197.1	P16112-4
ACAN	NM_001411097.1		c.7075G>A	p.Val2359Ile	missense	Exon 14 of 18	NP_001398026.1	A0A5K1VW97
ACAN	NM_013227.4		c.7075G>A	p.Val2359Ile	missense	Exon 14 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.7189G>A	p.Val2397Ile	missense	Exon 15 of 19	ENSP00000453581.2	P16112-4
ACAN	ENST00000439576.7	TSL:5	c.7075G>A	p.Val2359Ile	missense	Exon 14 of 18	ENSP00000387356.2	P16112-1
ACAN	ENST00000561243.7	TSL:5	c.7075G>A	p.Val2359Ile	missense	Exon 14 of 18	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000740

AC:

183

AN:

247260

AF XY:

0.000714

show subpopulations

Gnomad AFR exome

AF:

0.000262

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.000666

GnomAD4 exome

AF:

0.00120

AC:

1758

AN:

1461218

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

852

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33470

American (AMR)

AF:

0.000985

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000336

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00143

AC:

1587

AN:

1111734

Other (OTH)

AF:

0.00116

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

110

219

329

438

548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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:

0.000880

AC:

134

AN:

152328

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41576

American (AMR)

AF:

0.00196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00135

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00114

Hom.:

Bravo

AF:

0.000888

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00153

AC:

ExAC

AF:

0.000718

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00125

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.7

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.45

M_CAP

Benign

0.0035

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

PhyloP100

0.21

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.39

REVEL

Benign

0.041

Sift

Benign

0.84

Sift4G

Benign

0.78

Vest4

0.14

MVP

0.068

MPC

0.26

ClinPred

0.0084

GERP RS

3.7

Varity_R

0.019

gMVP

0.54

Mutation Taster

=100/0

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over