NM_005492.4:c.279C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005492.4(CST8):​c.279C>A​(p.Ser93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,060 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 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CST8
NM_005492.4 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.798
Variant links:
Genes affected
CST8 (HGNC:2480): (cystatin 8) 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 similar to type 2 cystatins. The encoded protein exhibits highly tissue-specific expression in the reproductive tract, suggesting implicit roles in reproduction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.024107695).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CST8NM_005492.4 linkc.279C>A p.Ser93Arg missense_variant Exon 3 of 4 ENST00000246012.2 NP_005483.1 O60676A0A384MDQ4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CST8ENST00000246012.2 linkc.279C>A p.Ser93Arg missense_variant Exon 3 of 4 1 NM_005492.4 ENSP00000246012.1 O60676
CST8ENST00000449810.5 linkc.279C>A p.Ser93Arg missense_variant Exon 3 of 4 3 ENSP00000399144.1 A2A2N0
ENSG00000260202ENST00000619495.1 linkn.439-11242G>T intron_variant Intron 1 of 1 4

Frequencies

GnomAD3 genomes
AF:
0.000645
AC:
98
AN:
151990
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000917
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:
0.000191
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000366
AC:
92
AN:
251408
Hom.:
0
AF XY:
0.000294
AC XY:
40
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00185
Gnomad AMR exome
AF:
0.000838
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000157
AC:
230
AN:
1460954
Hom.:
0
Cov.:
30
AF XY:
0.000144
AC XY:
105
AN XY:
726866
show subpopulations
Gnomad4 AFR exome
AF:
0.00140
Gnomad4 AMR exome
AF:
0.000827
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000102
Gnomad4 OTH exome
AF:
0.000497
GnomAD4 genome
AF:
0.000644
AC:
98
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.000605
AC XY:
45
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00169
Gnomad4 AMR
AF:
0.000916
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000246
Hom.:
0
Bravo
AF:
0.000737
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000321
AC:
39
EpiCase
AF:
0.000109
EpiControl
AF:
0.000474

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 12, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.279C>A (p.S93R) alteration is located in exon 3 (coding exon 2) of the CST8 gene. This alteration results from a C to A substitution at nucleotide position 279, causing the serine (S) at amino acid position 93 to be replaced by an arginine (R). 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
Pathogenic
0.96
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
.;T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.0099
T
MetaRNN
Benign
0.024
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
.;M
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Benign
0.19
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.010
D;D
Polyphen
1.0
.;D
Vest4
0.73
MutPred
0.85
Loss of phosphorylation at S93 (P = 0.0716);Loss of phosphorylation at S93 (P = 0.0716);
MVP
0.35
MPC
0.0036
ClinPred
0.058
T
GERP RS
3.4
Varity_R
0.83
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs138711661; hg19: chr20-23473642; API