Genetic Variant CST2:p.Asp86His (chr20-23825296-C-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001322.3(CST2):c.256G>C(p.Asp86His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,486,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D86N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CST2
NM_001322.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.874

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27880457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322.3. 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
	CST2	NM_001322.3	MANE Select	c.256G>C	p.Asp86His	missense	Exon 2 of 3	NP_001313.1	P09228

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST2	ENST00000304725.3	TSL:1 MANE Select	c.256G>C	p.Asp86His	missense	Exon 2 of 3	ENSP00000307540.2	P09228

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000268

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000323

AC:

AN:

247410

AF XY:

0.0000448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1373178

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

679660

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30686

American (AMR)

AF:

0.00

AC:

AN:

40108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24208

East Asian (EAS)

AF:

0.00

AC:

AN:

35300

South Asian (SAS)

AF:

0.000274

AC:

AN:

69356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5476

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1062360

Other (OTH)

AF:

0.00

AC:

AN:

55944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

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:

0.00000886

AC:

AN:

112888

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

55094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29238

American (AMR)

AF:

0.00

AC:

AN:

10400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3948

South Asian (SAS)

AF:

0.000268

AC:

AN:

3730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52110

Other (OTH)

AF:

0.00

AC:

AN:

1412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.78

M_CAP

Benign

0.0012

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.6

PhyloP100

-0.87

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.025

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.35

MutPred

0.50

Gain of MoRF binding (P = 0.1819)

MVP

0.32

MPC

0.0098

ClinPred

0.95

GERP RS

1.3

Varity_R

0.19

gMVP

0.25

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over