Genetic Variant NM_001750.7:c.2032G>C (chr5-96765320-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001750.7(CAST):c.2032G>C(p.Val678Leu) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000051 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAST
NM_001750.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

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]

CAST links:

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]

ERAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7 link	c.2032G>C	p.Val678Leu	missense_variant	Exon 26 of 32	ENST00000675179.1	NP_001741.4	P20810-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1 link	c.2032G>C	p.Val678Leu	missense_variant	Exon 26 of 32		NM_001750.7	ENSP00000501872.1		P20810-6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

33998

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000511

AC:

AN:

332886

Hom.:

Cov.:

AF XY:

0.0000490

AC XY:

AN XY:

183648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000633

Gnomad4 NFE exome

AF:

0.0000680

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

33998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

15610

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1909G>C (p.V637L) alteration is located in exon 24 (coding exon 24) of the CAST gene. This alteration results from a G to C substitution at nucleotide position 1909, causing the valine (V) at amino acid position 637 to be replaced by a leucine (L). 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

0.57

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;.;.;.;.;T;T;T;.;.;T;T;T;.;.;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.50

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Pathogenic

3.2

.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.3

N;N;N;N;N;N;.;N;N;N;N;N;N;N;N;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;.

Sift4G

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0

D;D;.;.;.;P;P;P;.;.;P;.;D;.;P;.

Vest4

0.46

MutPred

0.50

.;.;.;Loss of methylation at K655 (P = 0.0354);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.74

MPC

0.12

ClinPred

0.97

GERP RS

4.9

Varity_R

0.29

gMVP

0.093

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over