rs2882676

chr15-88857108-A-Cchr15-88857108-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369268.1(ACAN):c.4523A>C(p.Glu1508Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 1,612,950 control chromosomes in the GnomAD database, including 297,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22314 hom., cov: 31)
  • Exomes 𝑓: 0.60 (275047 hom.)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0151356E-6).
• BP6: Variant 15-88857108-A-C is Benign according to our data. Variant chr15-88857108-A-C is described in ClinVar as [Benign]. Clinvar id is 283836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88857108-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAN	NM_001369268.1	c.4523A>C	p.Glu1508Ala	missense_variant	12/19	ENST00000560601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAN	ENST00000560601.4	c.4523A>C	p.Glu1508Ala	missense_variant	12/19	3	NM_001369268.1	P1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80012 AN: 151262 Hom.: 22317 Cov.: 31

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.553

GnomAD3 exomes AF: 0.525 AC: 130849 AN: 249176 Hom.: 37429 AF XY: 0.538 AC XY: 72778 AN XY: 135202

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.506

Gnomad FIN exome AF: 0.588

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.605 AC: 883519 AN: 1461570 Hom.: 275047 Cov.: 80 AF XY: 0.604 AC XY: 438969 AN XY: 727070

Gnomad4 AFR exome AF: 0.367

Gnomad4 AMR exome AF: 0.330

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.647

Gnomad4 OTH exome AF: 0.577

GnomAD4 genome AF: 0.529 AC: 80019 AN: 151380 Hom.: 22314 Cov.: 31 AF XY: 0.521 AC XY: 38560 AN XY: 73960

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.599

Gnomad4 NFE AF: 0.645

Gnomad4 OTH AF: 0.552

Alfa AF: 0.604 Hom.: 52218

Bravo AF: 0.505

TwinsUK AF: 0.665 AC: 2464

ALSPAC AF: 0.655 AC: 2523

ESP6500AA AF: 0.393 AC: 1469

ESP6500EA AF: 0.649 AC: 5322

ExAC AF: 0.534 AC: 64560

Asia WGS AF: 0.412 AC: 1432 AN: 3478

EpiCase AF: 0.640

EpiControl AF: 0.642

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 09, 2015

- -

Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

This variant is associated with the following publications: (PMID: 17317784) -

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	6.7
Dann	Benign	0.68
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.50	T;T;T;T;T;.
MetaRNN	Benign	0.0000060	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.36	T
Vest4		0.045, 0.058, 0.056, 0.049, 0.026
MPC		0.26
ClinPred		0.0047	T
GERP RS		-2.1
Varity_R		0.039
gMVP		0.20

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: rs2882676; hg19: chr15-89400339; COSMIC: COSV61356013;