15-88856926-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001369268.1(ACAN):c.4341G>C(p.Glu1447Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 131,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1447K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.07

Publications

3 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):

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005847603).

BP6

Variant 15-88856926-G-C is Benign according to our data. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88856926-G-C is described in CliVar as Likely_benign. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1 link	c.4341G>C	p.Glu1447Asp	missense_variant	Exon 12 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.4341G>C	p.Glu1447Asp	missense_variant	Exon 12 of 19	3	NM_001369268.1	ENSP00000453581.2		H0YMF1

Frequencies

GnomAD3 genomes

AF:

0.000535

AC:

AN:

130954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000438

Gnomad ASJ

AF:

0.000319

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.00102

Gnomad FIN

AF:

0.000547

Gnomad MID

AF:

0.00543

Gnomad NFE

AF:

0.000217

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000242

AC:

AN:

248098

AF XY:

0.0000297

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000188

AC:

AN:

1437086

Hom.:

Cov.:

AF XY:

0.0000224

AC XY:

AN XY:

715296

show subpopulations

African (AFR)

AF:

0.000154

AC:

AN:

32476

American (AMR)

AF:

0.0000230

AC:

AN:

43524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24988

East Asian (EAS)

AF:

0.0000519

AC:

AN:

38546

South Asian (SAS)

AF:

0.0000587

AC:

AN:

85228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.0000100

AC:

AN:

1095642

Other (OTH)

AF:

0.0000513

AC:

AN:

58502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000534

AC:

AN:

131048

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

64624

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00104

AC:

AN:

34484

American (AMR)

AF:

0.000438

AC:

AN:

13692

Ashkenazi Jewish (ASJ)

AF:

0.000319

AC:

AN:

3136

East Asian (EAS)

AF:

0.000967

AC:

AN:

4136

South Asian (SAS)

AF:

0.00102

AC:

AN:

3924

European-Finnish (FIN)

AF:

0.000547

AC:

AN:

9142

Middle Eastern (MID)

AF:

0.00575

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000217

AC:

AN:

59810

Other (OTH)

AF:

0.00

AC:

AN:

1840

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.281

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:

0.000959

Hom.:

ExAC

AF:

0.000555

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.6% of African chromosomes in ExAC, frequency high for disorder -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0010

(source)

DANN

Benign

0.25

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.29

T;T;T;T;T;.

M_CAP

Benign

0.079

MetaRNN

Benign

0.0058

T;T;T;T;T;T

MetaSVM

Benign

-0.64

PhyloP100

-4.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.010

.;N;.;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.54

.;T;.;T;T;T

Sift4G

Benign

0.63

.;T;T;T;T;T

Vest4

0.029, 0.032, 0.036, 0.037, 0.022

MutPred

0.27

Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);.;Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);

MVP

0.14

MPC

0.18

ClinPred

0.023

GERP RS

-5.3

Varity_R

0.032

gMVP

0.055

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over