NM_001369268.1:c.47C>T

Variant names:

• chr15-88836253-C-T
• rs1325083323
• NM_001369268.1:c.47C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001369268.1(ACAN):​c.47C>T​(p.Ala16Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A16A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37
• Publications: 0 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):

• ACAN-related short stature spectrum

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• osteochondritis dissecans

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21034735).

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.47C>T	p.Ala16Val	missense	Exon 2 of 19	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.47C>T	p.Ala16Val	missense	Exon 2 of 18	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.47C>T	p.Ala16Val	missense	Exon 2 of 18	NP_037359.3	P16112-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	ENST00000560601.4	TSL:3 MANE Select	c.47C>T	p.Ala16Val	missense	Exon 2 of 19	ENSP00000453581.2	P16112-4
	ACAN	ENST00000558207.5	TSL:1	c.47C>T	p.Ala16Val	missense	Exon 2 of 10	ENSP00000453003.1	Q6PID9
	ACAN	ENST00000439576.7	TSL:5	c.47C>T	p.Ala16Val	missense	Exon 2 of 18	ENSP00000387356.2	P16112-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249074 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461544 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111782

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.16
Sift	Uncertain	0.011	D
Sift4G	Benign	0.14	T
Polyphen		0.021	B
Vest4		0.54
MutPred		0.30		Loss of loop (P = 0.0804)
MVP		0.068
MPC		0.20
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.20
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1325083323; hg19: chr15-89379484;