Genetic Variant CST5:p.Cys46Arg (chr20-23879541-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001900.5(CST5):c.136T>C(p.Cys46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,613,572 control chromosomes in the GnomAD database, including 174,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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 UniProt.

Frequency

Genomes: 𝑓 0.54 ( 23272 hom., cov: 32)

Exomes 𝑓: 0.45 ( 151476 hom. )

Consequence

CST5
NM_001900.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.92

Variant links:

Genes affected

CST5 (HGNC:2477): (cystatin D) 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. 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 a protein found in saliva and tears. The encoded protein may play a protective role against proteinases present in the oral cavity. [provided by RefSeq, Jul 2008]

CST5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0220704E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST5	NM_001900.5 link	c.136T>C	p.Cys46Arg	missense_variant	Exon 1 of 3	ENST00000304710.5	NP_001891.2	P28325

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST5	ENST00000304710.5 link	c.136T>C	p.Cys46Arg	missense_variant	Exon 1 of 3	1	NM_001900.5	ENSP00000307132.4		P28325

Frequencies

GnomAD3 genomes

AF:

0.535

AC:

81230

AN:

151762

Hom.:

23230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.756

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.490

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.483

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.550

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.433

Gnomad OTH

AF:

0.478

GnomAD3 exomes

AF:

0.482

AC:

121082

AN:

251316

Hom.:

30495

AF XY:

0.470

AC XY:

63782

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.760

Gnomad AMR exome

AF:

0.567

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.480

Gnomad SAS exome

AF:

0.443

Gnomad FIN exome

AF:

0.540

Gnomad NFE exome

AF:

0.430

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.451

AC:

659059

AN:

1461694

Hom.:

151476

Cov.:

AF XY:

0.450

AC XY:

326915

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.766

Gnomad4 AMR exome

AF:

0.561

Gnomad4 ASJ exome

AF:

0.357

Gnomad4 EAS exome

AF:

0.463

Gnomad4 SAS exome

AF:

0.448

Gnomad4 FIN exome

AF:

0.527

Gnomad4 NFE exome

AF:

0.436

Gnomad4 OTH exome

AF:

0.456

GnomAD4 genome

AF:

0.535

AC:

81326

AN:

151878

Hom.:

23272

Cov.:

AF XY:

0.537

AC XY:

39829

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.756

Gnomad4 AMR

AF:

0.491

Gnomad4 ASJ

AF:

0.356

Gnomad4 EAS

AF:

0.482

Gnomad4 SAS

AF:

0.435

Gnomad4 FIN

AF:

0.550

Gnomad4 NFE

AF:

0.433

Gnomad4 OTH

AF:

0.474

Alfa

AF:

0.437

Hom.:

38140

Bravo

AF:

0.546

TwinsUK

AF:

0.439

AC:

1629

ALSPAC

AF:

0.435

AC:

1676

ESP6500AA

AF:

0.749

AC:

3301

ESP6500EA

AF:

0.435

AC:

3740

ExAC

AF:

0.483

AC:

58625

Asia WGS

AF:

0.473

AC:

1647

AN:

3478

EpiCase

AF:

0.413

EpiControl

AF:

0.417

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.021

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.027

DANN

Benign

0.11

DEOGEN2

Benign

0.034

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00012

LIST_S2

Benign

0.039

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.8

PrimateAI

Benign

0.28

PROVEAN

Benign

5.3

REVEL

Benign

0.016

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.016

MPC

0.0043

ClinPred

0.010

GERP RS

-0.40

Varity_R

0.10

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over