20-23633996-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000099.4(CST3):c.361G>C(p.Ala121Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A121V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CST3 NM_000099.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.11

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2671181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CST3	NM_000099.4	c.361G>C	p.Ala121Pro	missense_variant	3/3	ENST00000376925.8
CST3	NM_001288614.2	c.361G>C	p.Ala121Pro	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CST3	ENST00000376925.8	c.361G>C	p.Ala121Pro	missense_variant	3/3	1	NM_000099.4	P1
CST3	ENST00000398411.5	c.361G>C	p.Ala121Pro	missense_variant	3/4	1		P1
CST3	ENST00000398409.1	c.361G>C	p.Ala121Pro	missense_variant	4/4	3		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CST3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 121 of the CST3 protein (p.Ala121Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	9.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.94	P;P;P
Vest4		0.48
MutPred		0.58		Loss of catalytic residue at A121 (P = 0.0325);Loss of catalytic residue at A121 (P = 0.0325);Loss of catalytic residue at A121 (P = 0.0325);
MVP		0.31
MPC		1.2
ClinPred		0.52	D
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.78
gMVP		0.72

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: rs1394879622; hg19: chr20-23614633;