Variant 20-23635364-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000099.4(CST3):c.247G>A(p.Val83Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000066 ( 0 hom. )

Consequence

CST3
NM_000099.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CST3	NM_000099.4 link	c.247G>A	p.Val83Ile	missense_variant	2/3	ENST00000376925.8	NP_000090.1	P01034A0A0K0K1J1
CST3	NM_001288614.2 link	c.247G>A	p.Val83Ile	missense_variant	2/4		NP_001275543.1	P01034A0A0K0K1J1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CST3	ENST00000376925.8 link	c.247G>A	p.Val83Ile	missense_variant	2/3	1	NM_000099.4	ENSP00000366124.3	P01034
CST3	ENST00000398411.5 link	c.247G>A	p.Val83Ile	missense_variant	2/4	1		ENSP00000381448.1	P01034
CST3	ENST00000398409.1 link	c.247G>A	p.Val83Ile	missense_variant	3/4	3		ENSP00000381446.1	P01034

Frequencies

GnomAD3 genomes

AF:

0.0000433

AC:

AN:

92386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000657

AC:

AN:

1369240

Hom.:

Cov.:

AF XY:

0.00000884

AC XY:

AN XY:

678758

show subpopulations

Gnomad4 AFR exome

AF:

0.0000334

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000281

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000472

Gnomad4 OTH exome

AF:

0.0000181

GnomAD4 genome

AF:

0.0000433

AC:

AN:

92386

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

45342

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 12, 2023

PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;T

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.89

.;.;D

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.5

H;H;H

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.94

N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.38

MutPred

0.79

Loss of MoRF binding (P = 0.1141);Loss of MoRF binding (P = 0.1141);Loss of MoRF binding (P = 0.1141);

MVP

0.47

MPC

1.2

ClinPred

0.97

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.74

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over