15-88859008-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001369268.1(ACAN):c.6423T>C(p.Leu2141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,613,796 control chromosomes in the GnomAD database, including 486,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (47112 hom., cov: 32)
  • Exomes 𝑓: 0.77 (439201 hom.)
• Consequence: ACAN NM_001369268.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.81

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 15-88859008-T-C is Benign according to our data. Variant chr15-88859008-T-C is described in ClinVar as [Benign]. Clinvar id is 1188994.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-88859008-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAN	NM_001369268.1	c.6423T>C	p.Leu2141=	synonymous_variant	12/19	ENST00000560601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAN	ENST00000560601.4	c.6423T>C	p.Leu2141=	synonymous_variant	12/19	3	NM_001369268.1	P1

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119292 AN: 152052 Hom.: 47083 Cov.: 32

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.785

GnomAD3 exomes AF: 0.730 AC: 181887 AN: 249080 Hom.: 67644 AF XY: 0.733 AC XY: 99039 AN XY: 135168

Gnomad AFR exome AF: 0.851

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.586

Gnomad SAS exome AF: 0.682

Gnomad FIN exome AF: 0.713

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.772 AC: 1128855 AN: 1461626 Hom.: 439201 Cov.: 83 AF XY: 0.770 AC XY: 559774 AN XY: 727092

Gnomad4 AFR exome AF: 0.848

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.785

Gnomad4 EAS exome AF: 0.537

Gnomad4 SAS exome AF: 0.682

Gnomad4 FIN exome AF: 0.710

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.768

GnomAD4 genome AF: 0.784 AC: 119371 AN: 152170 Hom.: 47112 Cov.: 32 AF XY: 0.774 AC XY: 57600 AN XY: 74398

Gnomad4 AFR AF: 0.848

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.786

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.694

Gnomad4 FIN AF: 0.717

Gnomad4 NFE AF: 0.797

Gnomad4 OTH AF: 0.782

Alfa AF: 0.789 Hom.: 71051

Bravo AF: 0.782

Asia WGS AF: 0.676 AC: 2352 AN: 3478

EpiCase AF: 0.794

EpiControl AF: 0.800

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Osteochondritis dissecans Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Spondyloepiphyseal dysplasia, Kimberley type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.11
Dann	Benign	0.28

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: rs1042631; hg19: chr15-89402239; COSMIC: COSV61355541;