dbSNP rs7733671: CAST:c.75+2068G>A (chr5-96664565-G-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+2068G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 151,974 control chromosomes in the GnomAD database, including 11,224 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 0.34 ( 11224 hom., cov: 31)

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.42

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:

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=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 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+2068G>A	intron	N/A	NP_001741.4
CAST	NM_001042441.3		c.75+2068G>A	intron	N/A	NP_001035906.1
CAST	NM_001042442.3		c.75+2068G>A	intron	N/A	NP_001035907.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.75+2068G>A	intron	N/A	ENSP00000501872.1
CAST	ENST00000338252.7	TSL:1	c.-175+2400G>A	intron	N/A	ENSP00000343421.3
CAST	ENST00000508830.5	TSL:5	c.75+2068G>A	intron	N/A	ENSP00000425721.1

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51210

AN:

151858

Hom.:

11192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.620

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.333

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.316

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

GnomAD4 genome

AF:

0.337

AC:

51291

AN:

151974

Hom.:

11224

Cov.:

AF XY:

0.335

AC XY:

24897

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.620

AC:

25695

AN:

41442

American (AMR)

AF:

0.248

AC:

3786

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

925

AN:

3466

East Asian (EAS)

AF:

0.333

AC:

1719

AN:

5162

South Asian (SAS)

AF:

0.314

AC:

1512

AN:

4816

European-Finnish (FIN)

AF:

0.181

AC:

1916

AN:

10566

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.216

AC:

14693

AN:

67932

Other (OTH)

AF:

0.317

AC:

669

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1491

2982

4473

5964

7455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.252

Hom.:

3212

Bravo

AF:

0.354

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.13

(source)

DANN

Benign

0.13

PhyloP100

-1.4

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