rs150555123

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

ACAN
NM_001369268.1 missense

Scores

1
16

Clinical Significance

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

Conservation

PhyloP100: 0.206
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 id is 445914.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACANNM_001369268.1 linkuse as main transcriptc.7189G>A p.Val2397Ile missense_variant 15/19 ENST00000560601.4 NP_001356197.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACANENST00000560601.4 linkuse as main transcriptc.7189G>A p.Val2397Ile missense_variant 15/193 NM_001369268.1 ENSP00000453581.2 H0YMF1

Frequencies

GnomAD3 genomes
AF:
0.000880
AC:
134
AN:
152212
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.000740
AC:
183
AN:
247260
Hom.:
1
AF XY:
0.000714
AC XY:
96
AN XY:
134486
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 SAS exome
AF:
0.000360
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.:
1
Cov.:
31
AF XY:
0.00117
AC XY:
852
AN XY:
726884
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.000985
Gnomad4 ASJ exome
AF:
0.000536
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000336
Gnomad4 FIN exome
AF:
0.0000751
Gnomad4 NFE exome
AF:
0.00143
Gnomad4 OTH exome
AF:
0.00116
GnomAD4 genome
AF:
0.000880
AC:
134
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.000779
AC XY:
58
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00135
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00117
Hom.:
0
Bravo
AF:
0.000888
TwinsUK
AF:
0.00270
AC:
10
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000232
AC:
1
ESP6500EA
AF:
0.00153
AC:
13
ExAC
AF:
0.000718
AC:
87
Asia WGS
AF:
0.000577
AC:
2
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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 27, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 31, 2017- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024ACAN: BP4 -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The 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
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 04, 2023Variant 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
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
2.7
DANN
Uncertain
0.98
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.45
T;T;T;T;T;.
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.020
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.32
T
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
T
GERP RS
3.7
Varity_R
0.019
gMVP
0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150555123; hg19: chr15-89414741; COSMIC: COSV104419334; COSMIC: COSV104419334; API