20-23637790-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000099.4(CST3):c.73G>A(p.Ala25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,523,760 control chromosomes in the GnomAD database, including 35,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3317 hom., cov: 33)

Exomes 𝑓: 0.21 ( 32071 hom. )

Consequence

CST3
NM_000099.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: -0.602

Publications

87 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:

ENSG00000286117 (HGNC:):

ENSG00000286117 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0043253005).

BP6

Variant 20-23637790-C-T is Benign according to our data. Variant chr20-23637790-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST3	NM_000099.4 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 3	ENST00000376925.8	NP_000090.1
CST3	NM_001288614.2 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 4		NP_001275543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CST3	ENST00000376925.8 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 3	1	NM_000099.4	ENSP00000366124.3
CST3	ENST00000398411.5 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 4	1		ENSP00000381448.1
CST3	ENST00000398409.1 link	c.73G>A	p.Ala25Thr	missense_variant	Exon 2 of 4	3		ENSP00000381446.1
ENSG00000286117	ENST00000801340.1 link	n.120+280C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30788

AN:

152002

Hom.:

3319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.0901

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.316

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.154

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.190

GnomAD2 exomes

AF:

0.202

AC:

24976

AN:

123942

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.243

Gnomad AMR exome

AF:

0.0941

Gnomad ASJ exome

AF:

0.164

Gnomad EAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.215

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.213

AC:

292258

AN:

1371652

Hom.:

32071

Cov.:

AF XY:

0.216

AC XY:

145909

AN XY:

676174

show subpopulations

African (AFR)

AF:

0.225

AC:

6311

AN:

28098

American (AMR)

AF:

0.0995

AC:

3296

AN:

33118

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

4010

AN:

24146

East Asian (EAS)

AF:

0.128

AC:

4151

AN:

32460

South Asian (SAS)

AF:

0.293

AC:

22448

AN:

76574

European-Finnish (FIN)

AF:

0.222

AC:

10608

AN:

47796

Middle Eastern (MID)

AF:

0.147

AC:

590

AN:

4014

European-Non Finnish (NFE)

AF:

0.215

AC:

229346

AN:

1068752

Other (OTH)

AF:

0.203

AC:

11498

AN:

56694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

12752

25504

38257

51009

63761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8076

16152

24228

32304

40380

<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:

0.202

AC:

30789

AN:

152108

Hom.:

3317

Cov.:

AF XY:

0.203

AC XY:

15117

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.214

AC:

8877

AN:

41512

American (AMR)

AF:

0.133

AC:

2035

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

563

AN:

3468

East Asian (EAS)

AF:

0.120

AC:

620

AN:

5150

South Asian (SAS)

AF:

0.315

AC:

1524

AN:

4832

European-Finnish (FIN)

AF:

0.227

AC:

2407

AN:

10598

Middle Eastern (MID)

AF:

0.155

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.210

AC:

14240

AN:

67940

Other (OTH)

AF:

0.188

AC:

396

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1255

2510

3764

5019

6274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.196

Hom.:

1036

Bravo

AF:

0.190

TwinsUK

AF:

0.210

AC:

777

ALSPAC

AF:

0.221

AC:

853

ESP6500AA

AF:

0.184

AC:

727

ESP6500EA

AF:

0.175

AC:

1322

ExAC

AF:

0.120

AC:

9151

Asia WGS

AF:

0.184

AC:

637

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Age related macular degeneration 11

Pathogenic:1Benign:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

NM_000099.2:c.73G>A in the gene CST3 has an allele frequency of 0.297 in South Asian subpopulation in the gnomAD database. A total of 3515 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1; BS2. -

Feb 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.229, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Hereditary cerebral amyloid angiopathy, Icelandic type;C2677774:Age related macular degeneration 11

Benign:1

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cerebral amyloid angiopathy, Icelandic type

Benign:1

Apr 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.4

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.33

.;.;T

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

L;L;L

PhyloP100

-0.60

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.016

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.094

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.019

MPC

0.42

ClinPred

0.00054

GERP RS

-1.6

PromoterAI

-0.0057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.58

Mutation Taster

=97/3

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over