chr20-23633113-G-A

Variant names:

• chr20-23633113-G-A
• rs2424577
• ENST00000398411.5:c.*2+801C>T

Variant summary

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

The ENST00000398411.5(CST3):​c.*2+801C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,988 control chromosomes in the GnomAD database, including 23,545 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 0.54 (23545 hom., cov: 31)
• Consequence: CST3 ENST00000398411.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.282
• Publications: 22 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST3	NM_001288614.2	c.*2+801C>T		intron_variant	Intron 3 of 3		NP_001275543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST3	ENST00000398411.5	c.*2+801C>T		intron_variant	Intron 3 of 3	1		ENSP00000381448.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82143 AN: 151870 Hom.: 23537 Cov.: 31

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.566

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.541 AC: 82158 AN: 151988 Hom.: 23545 Cov.: 31 AF XY: 0.545 AC XY: 40503 AN XY: 74288

African (AFR) AF: 0.329 AC: 13647 AN: 41460

American (AMR) AF: 0.655 AC: 10013 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2137 AN: 3468

East Asian (EAS) AF: 0.663 AC: 3407 AN: 5142

South Asian (SAS) AF: 0.472 AC: 2272 AN: 4814

European-Finnish (FIN) AF: 0.668 AC: 7046 AN: 10554

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41630 AN: 67958

Other (OTH) AF: 0.562 AC: 1185 AN: 2108

Alfa AF: 0.592 Hom.: 115062

Bravo AF: 0.534

Asia WGS AF: 0.544 AC: 1895 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.26
DANN	Benign	0.43
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs2424577; hg19: chr20-23613750;