20-23632100-C-T

Variant names:

• chr20-23632100-C-T
• rs911119
• ENST00000398411.5:c.*2+1814G>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.*2+1814G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 151,942 control chromosomes in the GnomAD database, including 43,002 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 0.75 (42962 hom., cov: 30)
  • Exomes 𝑓: 0.81 (40 hom.)
• Consequence: CST3 NM_001288614.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 50 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)

ENSG00000270001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 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.*2+1814G>A		intron	N/A	NP_001275543.1	P01034

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000398411.5	TSL:1	c.*2+1814G>A		intron	N/A	ENSP00000381448.1	P01034
	ENSG00000270001	ENST00000602977.1	TSL:6	n.217G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113335 AN: 151704 Hom.: 42938 Cov.: 30

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.840

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.762

GnomAD4 exome AF: 0.811 AC: 99 AN: 122 Hom.: 40 Cov.: 0 AF XY: 0.762 AC XY: 61 AN XY: 80

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.853 AC: 29 AN: 34

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.784 AC: 58 AN: 74

Other (OTH) AF: 1.00 AC: 8 AN: 8

GnomAD4 genome AF: 0.747 AC: 113398 AN: 151820 Hom.: 42962 Cov.: 30 AF XY: 0.748 AC XY: 55489 AN XY: 74172

African (AFR) AF: 0.633 AC: 26177 AN: 41384

American (AMR) AF: 0.840 AC: 12818 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2752 AN: 3464

East Asian (EAS) AF: 0.880 AC: 4488 AN: 5102

South Asian (SAS) AF: 0.682 AC: 3278 AN: 4806

European-Finnish (FIN) AF: 0.771 AC: 8154 AN: 10572

Middle Eastern (MID) AF: 0.826 AC: 238 AN: 288

European-Non Finnish (NFE) AF: 0.781 AC: 53049 AN: 67922

Other (OTH) AF: 0.765 AC: 1618 AN: 2114

Alfa AF: 0.821 Hom.: 37155

Bravo AF: 0.752

Asia WGS AF: 0.801 AC: 2787 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.85
PhyloP100		0.038
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: rs911119; hg19: chr20-23612737;