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5-96695865-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001750.7(CAST):c.168A>G(p.Gln56=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,608,786 control chromosomes in the GnomAD database, including 34,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2742 hom., cov: 31)
Exomes 𝑓: 0.20 ( 31447 hom. )

Consequence

CAST
NM_001750.7 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.01
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-96695865-A-G is Benign according to our data. Variant chr5-96695865-A-G is described in ClinVar as [Benign]. Clinvar id is 1192696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.01 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CASTNM_001750.7 linkuse as main transcriptc.168A>G p.Gln56= synonymous_variant 3/32 ENST00000675179.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CASTENST00000675179.1 linkuse as main transcriptc.168A>G p.Gln56= synonymous_variant 3/32 NM_001750.7 A2P20810-6

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.187
AC:
28353
AN:
151990
Hom.:
2739
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.132
Gnomad AMI
AF:
0.0866
Gnomad AMR
AF:
0.209
Gnomad ASJ
AF:
0.130
Gnomad EAS
AF:
0.234
Gnomad SAS
AF:
0.226
Gnomad FIN
AF:
0.257
Gnomad MID
AF:
0.187
Gnomad NFE
AF:
0.202
Gnomad OTH
AF:
0.174
GnomAD3 exomes
AF:
0.211
AC:
52378
AN:
247922
Hom.:
5775
AF XY:
0.212
AC XY:
28463
AN XY:
134504
show subpopulations
Gnomad AFR exome
AF:
0.128
Gnomad AMR exome
AF:
0.230
Gnomad ASJ exome
AF:
0.132
Gnomad EAS exome
AF:
0.236
Gnomad SAS exome
AF:
0.224
Gnomad FIN exome
AF:
0.254
Gnomad NFE exome
AF:
0.209
Gnomad OTH exome
AF:
0.200
GnomAD4 exome
AF:
0.205
AC:
298314
AN:
1456678
Hom.:
31447
Cov.:
30
AF XY:
0.206
AC XY:
149102
AN XY:
724680
show subpopulations
Gnomad4 AFR exome
AF:
0.123
Gnomad4 AMR exome
AF:
0.232
Gnomad4 ASJ exome
AF:
0.135
Gnomad4 EAS exome
AF:
0.261
Gnomad4 SAS exome
AF:
0.221
Gnomad4 FIN exome
AF:
0.254
Gnomad4 NFE exome
AF:
0.203
Gnomad4 OTH exome
AF:
0.196
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.186
AC:
28360
AN:
152108
Hom.:
2742
Cov.:
31
AF XY:
0.190
AC XY:
14144
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.132
Gnomad4 AMR
AF:
0.210
Gnomad4 ASJ
AF:
0.130
Gnomad4 EAS
AF:
0.234
Gnomad4 SAS
AF:
0.226
Gnomad4 FIN
AF:
0.257
Gnomad4 NFE
AF:
0.202
Gnomad4 OTH
AF:
0.173
Alfa
AF:
0.199
Hom.:
6186
Bravo
AF:
0.179
Asia WGS
AF:
0.259
AC:
901
AN:
3478
EpiCase
AF:
0.198
EpiControl
AF:
0.193

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
Cadd
Benign
1.1
Dann
Benign
0.59
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

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: rs9667; hg19: chr5-96031569; COSMIC: COSV57782905; COSMIC: COSV57782905; API