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):

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1 link	c.7189G>A	p.Val2397Ile	missense_variant	Exon 15 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.7189G>A	p.Val2397Ile	missense_variant	Exon 15 of 19	3	NM_001369268.1	ENSP00000453581.2		H0YMF1

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACAN: BP4 -

Inborn genetic diseases

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7075G>A (p.V2359I) alteration is located in exon 14 (coding exon 13) of the ACAN gene. This alteration results from a G to A substitution at nucleotide position 7075, causing the valine (V) at amino acid position 2359 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

May 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACAN c.7189G>A (p.Val2397Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 247260 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1184 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACAN causing ACAN-Related Disorders phenotype (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7189G>A in individuals affected with ACAN-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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

T;T;T;T;T;.

M_CAP

Benign

0.0035

MetaRNN

Benign

0.020

T;T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.21

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.39

.;N;.;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.84

.;T;.;T;T;T

Sift4G

Benign

0.78

.;T;T;T;T;T

Vest4

0.14, 0.16, 0.13, 0.19, 0.12

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

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