Genetic Variant CAST:c.138+6651C>T (chr5-96682252-C-T) – 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.138+6651C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,040 control chromosomes in the GnomAD database, including 9,188 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 0.31 ( 9188 hom., cov: 32)

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.921

Publications

13 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, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

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=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 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.138+6651C>T	intron	N/A	NP_001741.4
CAST	NM_001042441.3		c.138+6651C>T	intron	N/A	NP_001035906.1
CAST	NM_001042442.3		c.138+6651C>T	intron	N/A	NP_001035907.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.138+6651C>T	intron	N/A	ENSP00000501872.1
CAST	ENST00000338252.7	TSL:1	c.-112+6651C>T	intron	N/A	ENSP00000343421.3
CAST	ENST00000508830.5	TSL:5	c.138+6651C>T	intron	N/A	ENSP00000425721.1

Frequencies

GnomAD3 genomes

AF:

0.315

AC:

47785

AN:

151922

Hom.:

9160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.331

Gnomad SAS

AF:

0.312

Gnomad FIN

AF:

0.201

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.297

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

GnomAD4 genome

AF:

0.315

AC:

47865

AN:

152040

Hom.:

9188

Cov.:

AF XY:

0.313

AC XY:

23267

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.539

AC:

22333

AN:

41436

American (AMR)

AF:

0.240

AC:

3669

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

929

AN:

3470

East Asian (EAS)

AF:

0.331

AC:

1711

AN:

5174

South Asian (SAS)

AF:

0.313

AC:

1506

AN:

4818

European-Finnish (FIN)

AF:

0.201

AC:

2129

AN:

10572

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.215

AC:

14582

AN:

67966

Other (OTH)

AF:

0.299

AC:

630

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1485

2971

4456

5942

7427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.235

Hom.:

6846

Bravo

AF:

0.327

Asia WGS

AF:

0.319

AC:

1108

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

2.0

(source)

DANN

Benign

0.46

PhyloP100

-0.92

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