chr20-23635364-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ACys amyloidosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

CST3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

BS2

High AC in GnomAdExome4 at 9 AD gene.

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.247G>A	p.Val83Ile	missense	Exon 2 of 3	NP_000090.1	P01034
	CST3	NM_001288614.2		c.247G>A	p.Val83Ile	missense	Exon 2 of 4	NP_001275543.1	P01034

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CST3	ENST00000376925.8	TSL:1 MANE Select	c.247G>A	p.Val83Ile	missense	Exon 2 of 3	ENSP00000366124.3	P01034
CST3	ENST00000398411.5	TSL:1	c.247G>A	p.Val83Ile	missense	Exon 2 of 4	ENSP00000381448.1	P01034
CST3	ENST00000398409.1	TSL:3	c.247G>A	p.Val83Ile	missense	Exon 3 of 4	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

African (AFR)

AF:

0.0000334

AC:

AN:

29928

American (AMR)

AF:

0.00

AC:

AN:

39656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23464

East Asian (EAS)

AF:

0.00

AC:

AN:

34436

South Asian (SAS)

AF:

0.0000281

AC:

AN:

71158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

1059566

Other (OTH)

AF:

0.0000181

AC:

AN:

55298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000433

AC:

AN:

92386

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

45342

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

23782

American (AMR)

AF:

0.00

AC:

AN:

8832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2144

East Asian (EAS)

AF:

0.00

AC:

AN:

3244

South Asian (SAS)

AF:

0.00

AC:

AN:

3066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

41876

Other (OTH)

AF:

0.00

AC:

AN:

1142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.5

PhyloP100

2.7

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.94

REVEL

Benign

0.25

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.033

Polyphen

1.0

Vest4

0.38

MutPred

0.79

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

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over