Genetic Variant CST2:p.Val78Met (chr20-23825320-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001322.3(CST2):c.232G>A(p.Val78Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,455,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000031 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CST2
NM_001322.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Variant links:

Genes affected

CST2 (HGNC:2474): (cystatin SA) 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 secreted thiol protease inhibitor found at high levels in saliva, tears and seminal plasma. [provided by RefSeq, Jul 2008]

CST2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3891583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CST2	NM_001322.3 link	c.232G>A	p.Val78Met	missense_variant	Exon 2 of 3	ENST00000304725.3	NP_001313.1	P09228

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CST2	ENST00000304725.3 link	c.232G>A	p.Val78Met	missense_variant	Exon 2 of 3	1	NM_001322.3	ENSP00000307540.2		P09228

Frequencies

GnomAD3 genomes

AF:

0.0000315

AC:

AN:

95364

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000112

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:

0.0000229

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000889

AC:

AN:

224994

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122214

show subpopulations

Gnomad AFR exome

AF:

0.0000737

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000965

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000169

AC:

AN:

1359888

Hom.:

Cov.:

AF XY:

0.0000164

AC XY:

AN XY:

671748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000200

Gnomad4 OTH exome

AF:

0.0000183

GnomAD4 genome

AF:

0.0000315

AC:

AN:

95364

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

46582

show subpopulations

Gnomad4 AFR

AF:

0.0000411

Gnomad4 AMR

AF:

0.000112

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000229

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232G>A (p.V78M) alteration is located in exon 2 (coding exon 2) of the CST2 gene. This alteration results from a G to A substitution at nucleotide position 232, causing the valine (V) at amino acid position 78 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

0.049

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.093

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0014

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.5

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.17

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.40

MVP

0.38

MPC

0.011

ClinPred

0.99

GERP RS

2.4

Varity_R

0.39

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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