rs13038305

Variant names:

• chr20-23629625-C-T
• rs13038305
• ENST00000398411.5:c.*3-160G>A

Variant summary

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

The NM_001288614.2(CST3):​c.*3-160G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 151,800 control chromosomes in the GnomAD database, including 3,588 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 0.21 (3588 hom., cov: 31)
• Consequence: CST3 NM_001288614.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.358
• Publications: 24 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288614.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	NM_001288614.2		c.*3-160G>A		intron	N/A	NP_001275543.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000398411.5	TSL:1	c.*3-160G>A		intron	N/A	ENSP00000381448.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31993 AN: 151684 Hom.: 3582 Cov.: 31

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.0903

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.211 AC: 32021 AN: 151800 Hom.: 3588 Cov.: 31 AF XY: 0.212 AC XY: 15716 AN XY: 74150

African (AFR) AF: 0.226 AC: 9331 AN: 41342

American (AMR) AF: 0.143 AC: 2184 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3470

East Asian (EAS) AF: 0.116 AC: 597 AN: 5138

South Asian (SAS) AF: 0.321 AC: 1540 AN: 4800

European-Finnish (FIN) AF: 0.230 AC: 2414 AN: 10502

Middle Eastern (MID) AF: 0.153 AC: 44 AN: 288

European-Non Finnish (NFE) AF: 0.216 AC: 14707 AN: 67964

Other (OTH) AF: 0.202 AC: 427 AN: 2112

Alfa AF: 0.214 Hom.: 1971

Bravo AF: 0.199

Asia WGS AF: 0.186 AC: 646 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		-0.36
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: rs13038305; hg19: chr20-23610262;