20-23637788-GGC-CGT

Variant names:

• chr20-23637788-GGC-CGT
• NM_000099.4:c.73_75delGCCinsACG
• CST3 p.Ala25Thr

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000099.4(CST3):​c.73_75delGCCinsACG​(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CST3 NM_000099.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.804
• Publications: 0 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)

ENSG00000286117 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a mutagenesis_site Shows a dual distribution to the Golgi apparatus and to the mitochondria. (size 0) in uniprot entity CYTC_HUMAN

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000099.4. 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_000099.4	MANE Select	c.73_75delGCCinsACG	p.Ala25Thr	missense	N/A	NP_000090.1	P01034
	CST3	NM_001288614.2		c.73_75delGCCinsACG	p.Ala25Thr	missense	N/A	NP_001275543.1	P01034

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000376925.8	TSL:1 MANE Select	c.73_75delGCCinsACG	p.Ala25Thr	missense	N/A	ENSP00000366124.3	P01034
	CST3	ENST00000398411.5	TSL:1	c.73_75delGCCinsACG	p.Ala25Thr	missense	N/A	ENSP00000381448.1	P01034
	CST3	ENST00000398409.1	TSL:3	c.73_75delGCCinsACG	p.Ala25Thr	missense	N/A	ENSP00000381446.1	P01034

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-23618425;