chr15-88836064-G-T

Variant names:

• chr15-88836064-G-T
• rs938610
• NM_001369268.1:c.-7-136G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001369268.1(ACAN):​c.-7-136G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 479,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• 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: 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, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• spondyloepimetaphyseal dysplasia, aggrecan type

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.-7-136G>T		intron	N/A	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.-7-136G>T		intron	N/A	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.-7-136G>T		intron	N/A	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.-7-136G>T		intron	N/A	ENSP00000453581.2	P16112-4
	ACAN	ENST00000558207.5	TSL:1	c.-7-136G>T		intron	N/A	ENSP00000453003.1	Q6PID9
	ACAN	ENST00000439576.7	TSL:5	c.-7-136G>T		intron	N/A	ENSP00000387356.2	P16112-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000625 AC: 3 AN: 479764 Hom.: 0 AF XY: 0.0000120 AC XY: 3 AN XY: 250724

African (AFR) AF: 0.00 AC: 0 AN: 12922

American (AMR) AF: 0.00 AC: 0 AN: 20462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14310

East Asian (EAS) AF: 0.00 AC: 0 AN: 30866

South Asian (SAS) AF: 0.0000702 AC: 3 AN: 42716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2030

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 287770

Other (OTH) AF: 0.00 AC: 0 AN: 26754

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.041
DANN	Benign	0.48
PhyloP100		-1.5

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: rs938610; hg19: chr15-89379295;