chr15-88838822-G-A

Variant names:

Variant summary

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

The NM_001369268.1(ACAN):c.230G>A(p.Arg77His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. R77C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.13

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048683584).

BP6

Variant 15-88838822-G-A is Benign according to our data. Variant chr15-88838822-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446080.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00135 (205/152320) while in subpopulation NFE AF = 0.00176 (120/68024). AF 95% confidence interval is 0.00151. There are 0 homozygotes in GnomAd4. There are 118 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.230G>A	p.Arg77His	missense	Exon 3 of 19	NP_001356197.1	P16112-4
ACAN	NM_001411097.1		c.230G>A	p.Arg77His	missense	Exon 3 of 18	NP_001398026.1	A0A5K1VW97
ACAN	NM_013227.4		c.230G>A	p.Arg77His	missense	Exon 3 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.230G>A	p.Arg77His	missense	Exon 3 of 19	ENSP00000453581.2	P16112-4
ACAN	ENST00000558207.5	TSL:1	c.230G>A	p.Arg77His	missense	Exon 3 of 10	ENSP00000453003.1	Q6PID9
ACAN	ENST00000439576.7	TSL:5	c.230G>A	p.Arg77His	missense	Exon 3 of 18	ENSP00000387356.2	P16112-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00631

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00154

AC:

385

AN:

249238

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00683

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00134

AC:

1962

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

954

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00657

AC:

351

AN:

53398

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00137

AC:

1522

AN:

1111868

Other (OTH)

AF:

0.000944

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00135

AC:

205

AN:

152320

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41576

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00631

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00176

AC:

120

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00127

Hom.:

Bravo

AF:

0.000740

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00130

AC:

ExAC

AF:

0.00183

AC:

222

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

ACAN-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Osteochondritis dissecans (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.074

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.81

M_CAP

Benign

0.010

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

1.1

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.15

Sift

Benign

0.12

Sift4G

Benign

0.46

Polyphen

0.016

Vest4

0.23

MVP

0.19

MPC

0.25

ClinPred

0.031

GERP RS

4.8

Varity_R

0.081

gMVP

0.57

Mutation Taster

=98/2

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