20-23632100-C-T

Position:

• chr20-23632100-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ENSG00000270001 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CST3	NM_001288614.2	c.*2+1814G>A		intron_variant			NP_001275543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CST3	ENST00000398411.5	c.*2+1814G>A		intron_variant		1		ENSP00000381448.1
ENSG00000270001	ENST00000602977.1	n.217G>A		non_coding_transcript_exon_variant	1/1	6

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

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 1.00

Gnomad4 FIN exome AF: 0.853

Gnomad4 NFE exome AF: 0.784

Gnomad4 OTH exome AF: 1.00

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

Gnomad4 AFR AF: 0.633

Gnomad4 AMR AF: 0.840

Gnomad4 ASJ AF: 0.794

Gnomad4 EAS AF: 0.880

Gnomad4 SAS AF: 0.682

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.781

Gnomad4 OTH AF: 0.765

Alfa AF: 0.772 Hom.: 14353

Bravo AF: 0.752

Asia WGS AF: 0.801 AC: 2787 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.85

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: rs911119; hg19: chr20-23612737;