rs2424577

chr20-23633113-G-Achr20-23633113-G-C

Variant summary

Our verdict is Benign. Variant got -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

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=-0.92).
• 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/exons	MANE	UniProt
CST3	NM_001288614.2	c.*2+801C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CST3	ENST00000398411.5	c.*2+801C>T		intron_variant		1		P1

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

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.655

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.663

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.668

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.562

Alfa AF: 0.604 Hom.: 56161

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

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: rs2424577; hg19: chr20-23613750;