rs267604368

Positions:

• chr15-88858712-G-A
• chr15-88858712-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001369268.1(ACAN):​c.6127G>A​(p.Glu2043Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.6127G>A	p.Glu2043Lys	missense_variant	12/19	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.6127G>A	p.Glu2043Lys	missense_variant	12/19	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	.;T;.;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;.
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.2	.;D;.;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	.;D;.;D;D;D
Sift4G	Benign	0.45	.;T;T;T;T;T
Vest4		0.40, 0.34, 0.35, 0.31, 0.40
MutPred		0.49		Gain of methylation at E2043 (P = 0.0112);Gain of methylation at E2043 (P = 0.0112);.;Gain of methylation at E2043 (P = 0.0112);Gain of methylation at E2043 (P = 0.0112);Gain of methylation at E2043 (P = 0.0112);
MVP		0.14
MPC		0.82
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.39
gMVP		0.72

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: rs267604368; hg19: chr15-89401943;