dbSNP rs918629: CAST:c.-514+3723G>A (chr5-95965759-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_001423250.1(CAST):c.-514+3723G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,050 control chromosomes in the GnomAD database, including 13,970 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 0.39 ( 13970 hom., cov: 32)

Consequence

CAST
NM_001423250.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.159

Publications

6 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:

ENSG00000250955 (HGNC:):

ENSG00000250955 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=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
CAST	NM_001423250.1 link	c.-514+3723G>A	intron_variant	Intron 1 of 35	NP_001410179.1
CAST	NM_001423251.1 link	c.-727+3723G>A	intron_variant	Intron 1 of 34	NP_001410180.1
CAST	NM_001423253.1 link	c.-262+4173G>A	intron_variant	Intron 1 of 31	NP_001410182.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CAST	ENST00000502645.3 link	n.36+3723G>A	intron_variant	Intron 1 of 5	5
ENSG00000250955	ENST00000506070.1 link	n.319-508C>T	intron_variant	Intron 3 of 3	3
CAST	ENST00000511775.1 link	n.35+3723G>A	intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59602

AN:

151932

Hom.:

13932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.605

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.376

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.837

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.346

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.353

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

GnomAD4 genome

AF:

0.393

AC:

59688

AN:

152050

Hom.:

13970

Cov.:

AF XY:

0.400

AC XY:

29736

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.606

AC:

25117

AN:

41468

American (AMR)

AF:

0.377

AC:

5765

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

649

AN:

3466

East Asian (EAS)

AF:

0.836

AC:

4335

AN:

5188

South Asian (SAS)

AF:

0.458

AC:

2210

AN:

4826

European-Finnish (FIN)

AF:

0.346

AC:

3650

AN:

10540

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.248

AC:

16849

AN:

67958

Other (OTH)

AF:

0.351

AC:

740

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1670

3341

5011

6682

8352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.293

Hom.:

24002

Bravo

AF:

0.407

Asia WGS

AF:

0.642

AC:

2228

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.9

(source)

DANN

Benign

0.60

PhyloP100

0.16

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