15-88855176-C-T

Variant names:

• chr15-88855176-C-T
• rs3743398
• NM_001369268.1:c.2591C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369268.1(ACAN):​c.2591C>T​(p.Pro864Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,607,782 control chromosomes in the GnomAD database, including 28,870 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2112 hom., cov: 34)
  • Exomes 𝑓: 0.18 (26758 hom.)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.918
• Publications: 30 publications found

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]

ACAN Gene-Disease associations (from GenCC):

• osteochondritis dissecans

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• spondyloepiphyseal dysplasia, Kimberley type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spondyloepimetaphyseal dysplasia, aggrecan type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• short stature-advanced bone age-early-onset osteoarthritis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013746023).
• BP6: Variant 15-88855176-C-T is Benign according to our data. Variant chr15-88855176-C-T is described in ClinVar as Benign. ClinVar VariationId is 1229794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369268.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	NM_001369268.1	MANE Select	c.2591C>T	p.Pro864Leu	missense	Exon 12 of 19	NP_001356197.1
	ACAN	NM_001411097.1		c.2591C>T	p.Pro864Leu	missense	Exon 12 of 18	NP_001398026.1
	ACAN	NM_013227.4		c.2591C>T	p.Pro864Leu	missense	Exon 12 of 18	NP_037359.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	ENST00000560601.4	TSL:3 MANE Select	c.2591C>T	p.Pro864Leu	missense	Exon 12 of 19	ENSP00000453581.2
	ACAN	ENST00000439576.7	TSL:5	c.2591C>T	p.Pro864Leu	missense	Exon 12 of 18	ENSP00000387356.2
	ACAN	ENST00000561243.7	TSL:5	c.2591C>T	p.Pro864Leu	missense	Exon 12 of 18	ENSP00000453342.3

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22571 AN: 152174 Hom.: 2111 Cov.: 34

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.153 AC: 37481 AN: 245408 AF XY: 0.152

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.184 AC: 267560 AN: 1455490 Hom.: 26758 Cov.: 82 AF XY: 0.180 AC XY: 130183 AN XY: 723022

African (AFR) AF: 0.0342 AC: 1141 AN: 33358

American (AMR) AF: 0.106 AC: 4712 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4683 AN: 25794

East Asian (EAS) AF: 0.107 AC: 4249 AN: 39550

South Asian (SAS) AF: 0.0383 AC: 3284 AN: 85678

European-Finnish (FIN) AF: 0.217 AC: 11501 AN: 52944

Middle Eastern (MID) AF: 0.151 AC: 865 AN: 5740

European-Non Finnish (NFE) AF: 0.205 AC: 227198 AN: 1108002

Other (OTH) AF: 0.165 AC: 9927 AN: 60026

GnomAD4 genome AF: 0.148 AC: 22564 AN: 152292 Hom.: 2112 Cov.: 34 AF XY: 0.147 AC XY: 10922 AN XY: 74452

African (AFR) AF: 0.0425 AC: 1768 AN: 41580

American (AMR) AF: 0.144 AC: 2199 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 639 AN: 3468

East Asian (EAS) AF: 0.105 AC: 545 AN: 5182

South Asian (SAS) AF: 0.0362 AC: 175 AN: 4830

European-Finnish (FIN) AF: 0.232 AC: 2456 AN: 10590

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14196 AN: 68018

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.189 Hom.: 10639

Bravo AF: 0.137

TwinsUK AF: 0.215 AC: 798

ALSPAC AF: 0.206 AC: 794

ESP6500AA AF: 0.0346 AC: 138

ESP6500EA AF: 0.201 AC: 1673

ExAC AF: 0.151 AC: 18291

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (1)
-	-	1	Spondyloepimetaphyseal dysplasia, aggrecan type (1)
-	-	1	Spondyloepiphyseal dysplasia, Kimberley type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	0.029
Eigen_PC	Benign	0.0040
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.92
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.10
Sift	Benign	0.068	T
Sift4G	Uncertain	0.015	D
Vest4		0.058
MPC		0.78
ClinPred		0.056	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3743398; hg19: chr15-89398407; COSMIC: COSV61357166; COSMIC: COSV61357166;