rs6048952

Variant names:

• chr20-23626620-A-G
• rs6048952
• ENST00000398411.5:c.*2848T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001288614.2(CST3):​c.*2848T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 152,144 control chromosomes in the GnomAD database, including 6,138 homozygotes. 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: 𝑓 0.27 (6136 hom., cov: 33)
  • Exomes 𝑓: 0.20 (2 hom.)
• Consequence: CST3 NM_001288614.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.307

Genes affected

CST3 (HGNC:2475): (cystatin C) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes the most abundant extracellular inhibitor of cysteine proteases, which is found in high concentrations in biological fluids and is expressed in virtually all organs of the body. A mutation in this gene has been associated with amyloid angiopathy. Expression of this protein in vascular wall smooth muscle cells is severely reduced in both atherosclerotic and aneurysmal aortic lesions, establishing its role in vascular disease. In addition, this protein has been shown to have an antimicrobial function, inhibiting the replication of herpes simplex virus. Alternative splicing results in multiple transcript variants encoding a single protein. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST3	NM_001288614.2	c.*2848T>C		downstream_gene_variant			NP_001275543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST3	ENST00000398411.5	c.*2848T>C		downstream_gene_variant		1		ENSP00000381448.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40336 AN: 152006 Hom.: 6129 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.242

GnomAD4 exome AF: 0.200 AC: 4 AN: 20 Hom.: 2 AF XY: 0.286 AC XY: 4 AN XY: 14

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.265 AC: 40371 AN: 152124 Hom.: 6136 Cov.: 33 AF XY: 0.264 AC XY: 19664 AN XY: 74380

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.239

Alfa AF: 0.227 Hom.: 4237

Bravo AF: 0.261

Asia WGS AF: 0.196 AC: 681 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.85
DANN	Benign	0.29

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6048952; hg19: chr20-23607257;