Genetic Variant CAST:c.-406+26145T>C (chr5-96000627-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001423250.1(CAST):c.-406+26145T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 152,206 control chromosomes in the GnomAD database, including 733 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 0.069 ( 733 hom., cov: 32)

Consequence

CAST
NM_001423250.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.15

Publications

0 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:

LOC101929710 (HGNC:):

LOC101929710 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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
CAST	NM_001423250.1 link	c.-406+26145T>C	intron_variant	Intron 2 of 35	NP_001410179.1
CAST	NM_001423251.1 link	c.-727+38591T>C	intron_variant	Intron 1 of 34	NP_001410180.1
CAST	NM_001423253.1 link	c.-262+39041T>C	intron_variant	Intron 1 of 31	NP_001410182.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CAST	ENST00000502645.3 link	n.36+38591T>C	intron_variant	Intron 1 of 5	5
CAST	ENST00000511775.1 link	n.35+38591T>C	intron_variant	Intron 1 of 1	4
CAST	ENST00000718075.1 link	n.33+38591T>C	intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0688

AC:

10468

AN:

152088

Hom.:

726

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0895

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.0331

Gnomad SAS

AF:

0.0775

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.0592

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

GnomAD4 genome

AF:

0.0690

AC:

10498

AN:

152206

Hom.:

733

Cov.:

AF XY:

0.0701

AC XY:

5215

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.177

AC:

7346

AN:

41484

American (AMR)

AF:

0.0902

AC:

1378

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3470

East Asian (EAS)

AF:

0.0334

AC:

173

AN:

5180

South Asian (SAS)

AF:

0.0761

AC:

367

AN:

4824

European-Finnish (FIN)

AF:

0.0218

AC:

232

AN:

10626

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

733

AN:

68016

Other (OTH)

AF:

0.0591

AC:

125

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

452

905

1357

1810

2262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0556

Hom.:

Bravo

AF:

0.0780

Asia WGS

AF:

0.0740

AC:

256

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.44

(source)

DANN

Benign

0.40

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over