Genetic Variant CAST:c.75+2594C>A (chr5-96665091-C-A) – 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+2594C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 152,042 control chromosomes in the GnomAD database, including 33,253 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 0.65 ( 33253 hom., cov: 32)

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.240

Publications

8 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:

Genome browser will be placed here

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 (AFR) allele frequency at 95% confidence interval = 0.842 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+2594C>A	intron	N/A	NP_001741.4
CAST	NM_001042441.3		c.75+2594C>A	intron	N/A	NP_001035906.1
CAST	NM_001042442.3		c.75+2594C>A	intron	N/A	NP_001035907.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.75+2594C>A	intron	N/A	ENSP00000501872.1
CAST	ENST00000338252.7	TSL:1	c.-175+2926C>A	intron	N/A	ENSP00000343421.3
CAST	ENST00000508830.5	TSL:5	c.75+2594C>A	intron	N/A	ENSP00000425721.1

Frequencies

GnomAD3 genomes

AF:

0.645

AC:

97962

AN:

151924

Hom.:

33201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.850

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.685

Gnomad ASJ

AF:

0.453

Gnomad EAS

AF:

0.798

Gnomad SAS

AF:

0.629

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.605

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

GnomAD4 genome

AF:

0.645

AC:

98071

AN:

152042

Hom.:

33253

Cov.:

AF XY:

0.649

AC XY:

48215

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.850

AC:

35272

AN:

41506

American (AMR)

AF:

0.685

AC:

10469

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.453

AC:

1573

AN:

3470

East Asian (EAS)

AF:

0.798

AC:

4126

AN:

5170

South Asian (SAS)

AF:

0.629

AC:

3030

AN:

4820

European-Finnish (FIN)

AF:

0.569

AC:

6014

AN:

10566

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.527

AC:

35760

AN:

67908

Other (OTH)

AF:

0.603

AC:

1274

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1596

3192

4787

6383

7979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

770

1540

2310

3080

3850

<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:

0.606

Hom.:

11189

Bravo

AF:

0.660

Asia WGS

AF:

0.720

AC:

2502

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

4.3

(source)

DANN

Benign

0.47

PhyloP100

0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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