NM_001750.7:c.1897A>T

Variant summary

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

The NM_001750.7(CAST):​c.1897A>T​(p.Thr633Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T633M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CAST
NM_001750.7 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.964
Variant links:
Genes affected
CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]
ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

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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=0.06689).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASTNM_001750.7 linkc.1897A>T p.Thr633Ser missense_variant Exon 25 of 32 ENST00000675179.1 NP_001741.4 P20810-6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASTENST00000675179.1 linkc.1897A>T p.Thr633Ser missense_variant Exon 25 of 32 NM_001750.7 ENSP00000501872.1 P20810-6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1774A>T (p.T592S) alteration is located in exon 23 (coding exon 23) of the CAST gene. This alteration results from a A to T substitution at nucleotide position 1774, causing the threonine (T) at amino acid position 592 to be replaced by a serine (S). 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
Benign
0.095
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.010
DANN
Benign
0.82
DEOGEN2
Benign
0.030
.;.;.;.;.;T;T;T;.;.;T;T;T;.;.;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.67
T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.067
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.050
.;.;.;.;.;N;N;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.36
N;N;N;N;N;N;.;N;N;N;N;N;N;N;N;.
REVEL
Benign
0.042
Sift
Benign
0.75
T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;.
Sift4G
Benign
1.0
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.68
P;B;.;.;.;B;B;B;.;.;B;.;P;.;B;.
Vest4
0.084
MutPred
0.34
.;.;.;Loss of catalytic residue at T611 (P = 0.0295);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.39
MPC
0.034
ClinPred
0.14
T
GERP RS
-2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.017
gMVP
0.043

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.

Other links and lift over

dbSNP: rs962850208; hg19: chr5-96098041; API