rs16942341

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001369268.1(ACAN):​c.1221C>T​(p.Val407=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,614,024 control chromosomes in the GnomAD database, including 1,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 512 hom., cov: 33)
Exomes 𝑓: 0.033 ( 1346 hom. )

Consequence

ACAN
NM_001369268.1 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.745
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 15-88845674-C-T is Benign according to our data. Variant chr15-88845674-C-T is described in ClinVar as [Benign]. Clinvar id is 1206376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88845674-C-T is described in Lovd as [Benign]. Variant chr15-88845674-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.745 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACANNM_001369268.1 linkuse as main transcriptc.1221C>T p.Val407= synonymous_variant 7/19 ENST00000560601.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACANENST00000560601.4 linkuse as main transcriptc.1221C>T p.Val407= synonymous_variant 7/193 NM_001369268.1 P1

Frequencies

GnomAD3 genomes
AF:
0.0619
AC:
9428
AN:
152216
Hom.:
511
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.148
Gnomad AMI
AF:
0.0417
Gnomad AMR
AF:
0.0438
Gnomad ASJ
AF:
0.0504
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.0575
Gnomad FIN
AF:
0.0148
Gnomad MID
AF:
0.0823
Gnomad NFE
AF:
0.0267
Gnomad OTH
AF:
0.0598
GnomAD3 exomes
AF:
0.0376
AC:
9344
AN:
248452
Hom.:
330
AF XY:
0.0379
AC XY:
5113
AN XY:
134866
show subpopulations
Gnomad AFR exome
AF:
0.149
Gnomad AMR exome
AF:
0.0252
Gnomad ASJ exome
AF:
0.0511
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.0602
Gnomad FIN exome
AF:
0.0139
Gnomad NFE exome
AF:
0.0293
Gnomad OTH exome
AF:
0.0378
GnomAD4 exome
AF:
0.0334
AC:
48871
AN:
1461690
Hom.:
1346
Cov.:
32
AF XY:
0.0341
AC XY:
24795
AN XY:
727132
show subpopulations
Gnomad4 AFR exome
AF:
0.149
Gnomad4 AMR exome
AF:
0.0274
Gnomad4 ASJ exome
AF:
0.0497
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0618
Gnomad4 FIN exome
AF:
0.0145
Gnomad4 NFE exome
AF:
0.0289
Gnomad4 OTH exome
AF:
0.0423
GnomAD4 genome
AF:
0.0619
AC:
9429
AN:
152334
Hom.:
512
Cov.:
33
AF XY:
0.0623
AC XY:
4639
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.148
Gnomad4 AMR
AF:
0.0438
Gnomad4 ASJ
AF:
0.0504
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.0565
Gnomad4 FIN
AF:
0.0148
Gnomad4 NFE
AF:
0.0267
Gnomad4 OTH
AF:
0.0592
Alfa
AF:
0.0350
Hom.:
282
Bravo
AF:
0.0676
Asia WGS
AF:
0.0360
AC:
127
AN:
3478
EpiCase
AF:
0.0321
EpiControl
AF:
0.0345

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxJul 09, 2018- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Spondyloepiphyseal dysplasia, Kimberley type Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
1.1
DANN
Benign
0.32

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: rs16942341; hg19: chr15-89388905; COSMIC: COSV104419237; API