rs16942341

Positions:

• chr15-88845674-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.745

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]

ACMG classification

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
ACAN	NM_001369268.1	c.1221C>T	p.Val407=	synonymous_variant	7/19	ENST00000560601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAN	ENST00000560601.4	c.1221C>T	p.Val407=	synonymous_variant	7/19	3	NM_001369268.1	P1

Frequencies

GnomAD3 genomes AF: 0.0619 AC: 9428 AN: 152216 Hom.: 511 Cov.: 33

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

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

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

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint 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 submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Spondyloepiphyseal dysplasia, Kimberley type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 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

Other links and lift over

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