5-96762275-A-G

Position:

chr5-96762275-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001750.7(CAST):c.1835A>G(p.Lys612Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,600,692 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0060 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 14 hom. )

Consequence

CAST
NM_001750.7 missense, splice_region

Scores

Splicing: ADA: 0.001810

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.72

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004529983).

BP6

Variant 5-96762275-A-G is Benign according to our data. Variant chr5-96762275-A-G is described in ClinVar as [Benign]. Clinvar id is 709742.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00601 (915/152266) while in subpopulation AFR AF= 0.02 (830/41554). AF 95% confidence interval is 0.0188. There are 10 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7 linkuse as main transcript	c.1835A>G	p.Lys612Arg	missense_variant, splice_region_variant	25/32	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1 linkuse as main transcript	c.1835A>G	p.Lys612Arg	missense_variant, splice_region_variant	25/32		NM_001750.7	ENSP00000501872	A2	P20810-6

Frequencies

GnomAD3 genomes

AF:

0.00600

AC:

913

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00187

AC:

448

AN:

239302

Hom.:

AF XY:

0.00151

AC XY:

196

AN XY:

129716

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.000910

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000286

Gnomad SAS exome

AF:

0.00230

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000235

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000849

AC:

1229

AN:

1448426

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

613

AN XY:

720680

show subpopulations

Gnomad4 AFR exome

AF:

0.0214

Gnomad4 AMR exome

AF:

0.00122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.00242

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00601

AC:

915

AN:

152266

Hom.:

Cov.:

AF XY:

0.00576

AC XY:

429

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0200

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00670

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00208

AC:

253

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

CAST-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.030

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0045

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.89

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

REVEL

Benign

0.020

Sift

Benign

0.13

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

Sift4G

Benign

0.26

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

Polyphen

0.20

B;B;.;.;.;B;B;B;.;.;B;.;B;.;B;.

Vest4

0.096

MVP

0.49

MPC

0.068

ClinPred

0.020

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

Varity_R

0.037

gMVP

0.052

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.20

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: 1

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