Genetic Variant CAST:c.75+1325A>G (chr5-96663822-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001750.7(CAST):c.75+1325A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,990 control chromosomes in the GnomAD database, including 52,627 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.83 ( 52627 hom., cov: 29)

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0190

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST links:

CAST (HGNC:):

CAST links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	NM_001750.7	MANE Select	c.75+1325A>G	intron	N/A	NP_001741.4
CAST	NM_001042441.3		c.75+1325A>G	intron	N/A	NP_001035906.1
CAST	NM_001042442.3		c.75+1325A>G	intron	N/A	NP_001035907.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.75+1325A>G	intron	N/A	ENSP00000501872.1
CAST	ENST00000338252.7	TSL:1	c.-175+1657A>G	intron	N/A	ENSP00000343421.3
CAST	ENST00000508830.5	TSL:5	c.75+1325A>G	intron	N/A	ENSP00000425721.1

Frequencies

GnomAD3 genomes

AF:

0.826

AC:

125464

AN:

151872

Hom.:

52561

Cov.:

show subpopulations

Gnomad AFR

AF:

0.957

Gnomad AMI

AF:

0.671

Gnomad AMR

AF:

0.852

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.782

Gnomad FIN

AF:

0.763

Gnomad MID

AF:

0.709

Gnomad NFE

AF:

0.752

Gnomad OTH

AF:

0.790

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.826

AC:

125594

AN:

151990

Hom.:

52627

Cov.:

AF XY:

0.828

AC XY:

61479

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.957

AC:

39698

AN:

41484

American (AMR)

AF:

0.852

AC:

13018

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2367

AN:

3466

East Asian (EAS)

AF:

0.997

AC:

5149

AN:

5162

South Asian (SAS)

AF:

0.784

AC:

3775

AN:

4818

European-Finnish (FIN)

AF:

0.763

AC:

8014

AN:

10504

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.752

AC:

51088

AN:

67964

Other (OTH)

AF:

0.792

AC:

1665

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1029

2059

3088

4118

5147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

874

1748

2622

3496

4370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.765

Hom.:

72481

Bravo

AF:

0.838

Asia WGS

AF:

0.902

AC:

3136

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

6.7

(source)

DANN

Benign

0.50

PhyloP100

0.019

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over