rs6048952

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000398411.5(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 ENST00000398411.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.307
• Publications: 13 publications found

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]

CST3 Gene-Disease associations (from GenCC):

• ACys amyloidosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398411.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	NM_001288614.2		c.*2848T>C		downstream_gene	N/A	NP_001275543.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000398411.5	TSL:1	c.*2848T>C		downstream_gene	N/A	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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.222 AC: 4 AN: 18

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.407 AC: 16876 AN: 41480

American (AMR) AF: 0.166 AC: 2536 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 696 AN: 3466

East Asian (EAS) AF: 0.116 AC: 603 AN: 5176

South Asian (SAS) AF: 0.322 AC: 1550 AN: 4820

European-Finnish (FIN) AF: 0.232 AC: 2452 AN: 10578

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15022 AN: 67992

Other (OTH) AF: 0.239 AC: 505 AN: 2112

Alfa AF: 0.243 Hom.: 6996

Bravo AF: 0.261

Asia WGS AF: 0.196 AC: 681 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.85
DANN	Benign	0.29
PhyloP100		-0.31

Splicing

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

Other links and lift over

dbSNP: rs6048952; hg19: chr20-23607257;