20-23750859-T-C

Position:

chr20-23750859-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001898.3(CST1):c.8A>G(p.Gln3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,607,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

CST1
NM_001898.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.64

Variant links:

Genes affected

CST1 (HGNC:2473): (cystatin SN) 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 a cysteine proteinase inhibitor found in saliva, tears, urine, and seminal fluid. [provided by RefSeq, Jul 2008]

CST1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017624557).

BP6

Variant 20-23750859-T-C is Benign according to our data. Variant chr20-23750859-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3078397.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CST1	NM_001898.3 linkuse as main transcript	c.8A>G	p.Gln3Arg	missense_variant	1/3	ENST00000304749.7	NP_001889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CST1	ENST00000304749.7 linkuse as main transcript	c.8A>G	p.Gln3Arg	missense_variant	1/3	1	NM_001898.3	ENSP00000305731	P1
CST1	ENST00000398402.1 linkuse as main transcript	c.8A>G	p.Gln3Arg	missense_variant	2/4	5		ENSP00000381439	P1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000435

AC:

104

AN:

239008

Hom.:

AF XY:

0.000395

AC XY:

AN XY:

129142

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000210

Gnomad ASJ exome

AF:

0.00123

Gnomad EAS exome

AF:

0.0000564

Gnomad SAS exome

AF:

0.000340

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000645

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000382

AC:

556

AN:

1455612

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

289

AN XY:

723544

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.000274

Gnomad4 ASJ exome

AF:

0.00100

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000434

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.000377

Gnomad4 OTH exome

AF:

0.000582

GnomAD4 genome

AF:

0.000375

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000643

Hom.:

ExAC

AF:

0.000445

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.049

DANN

Benign

0.19

DEOGEN2

Benign

0.0080

T;T

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.00021

LIST_S2

Benign

0.16

.;T

M_CAP

Benign

0.0014

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.67

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.020

N;N

REVEL

Benign

0.0040

Sift

Benign

0.80

T;T

Sift4G

Benign

0.79

T;T

Polyphen

0.016

B;B

Vest4

0.038

MVP

0.040

MPC

0.0033

ClinPred

0.0038

GERP RS

-2.8

Varity_R

0.026

gMVP

0.12

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