chr5-96765218-C-T

Variant summary

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

The NM_001750.7(CAST):​c.1933-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,565,646 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0049 ( 5 hom., cov: 30)
Exomes 𝑓: 0.00044 ( 10 hom. )

Consequence

CAST
NM_001750.7 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.0003904
2

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.262
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]

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 (BayesDel_noAF=-0.61).
BP6
Variant 5-96765218-C-T is Benign according to our data. Variant chr5-96765218-C-T is described in ClinVar as [Benign]. Clinvar id is 716343.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00491 (742/151012) while in subpopulation AFR AF= 0.0171 (704/41160). AF 95% confidence interval is 0.0161. There are 5 homozygotes in gnomad4. There are 355 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CASTNM_001750.7 linkuse as main transcriptc.1933-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000675179.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CASTENST00000675179.1 linkuse as main transcriptc.1933-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant NM_001750.7 A2P20810-6

Frequencies

GnomAD3 genomes
AF:
0.00491
AC:
741
AN:
150898
Hom.:
5
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0171
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00186
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000209
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000295
Gnomad OTH
AF:
0.00385
GnomAD3 exomes
AF:
0.00131
AC:
318
AN:
243480
Hom.:
3
AF XY:
0.000957
AC XY:
126
AN XY:
131664
show subpopulations
Gnomad AFR exome
AF:
0.0174
Gnomad AMR exome
AF:
0.000976
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000695
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000899
Gnomad OTH exome
AF:
0.000678
GnomAD4 exome
AF:
0.000435
AC:
616
AN:
1414634
Hom.:
10
Cov.:
26
AF XY:
0.000377
AC XY:
266
AN XY:
706298
show subpopulations
Gnomad4 AFR exome
AF:
0.0148
Gnomad4 AMR exome
AF:
0.00100
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000131
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000130
Gnomad4 OTH exome
AF:
0.00118
GnomAD4 genome
AF:
0.00491
AC:
742
AN:
151012
Hom.:
5
Cov.:
30
AF XY:
0.00482
AC XY:
355
AN XY:
73658
show subpopulations
Gnomad4 AFR
AF:
0.0171
Gnomad4 AMR
AF:
0.00186
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.00381
Alfa
AF:
0.00237
Hom.:
3
Bravo
AF:
0.00577
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ERAP1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 20, 2020This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 24, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.61
CADD
Benign
4.1
DANN
Benign
0.64
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00039
dbscSNV1_RF
Benign
0.12
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113716524; hg19: chr5-96100922; API