dbSNP rs13362120: CAST:c.631-682T>C (chr5-96735490-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_001750.7(CAST):c.631-682T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,194 control chromosomes in the GnomAD database, including 5,319 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 0.25 ( 5319 hom., cov: 32)

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.585

Publications

19 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=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7 link	c.631-682T>C		intron_variant	Intron 9 of 31	ENST00000675179.1	NP_001741.4	P20810-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1 link	c.631-682T>C		intron_variant	Intron 9 of 31		NM_001750.7	ENSP00000501872.1		P20810-6
CAST	ENST00000508117.6 link	n.*155-682T>C		intron_variant	Intron 7 of 7	5		ENSP00000422466.1		D6RBZ8

Frequencies

GnomAD3 genomes

AF:

0.253

AC:

38483

AN:

152076

Hom.:

5313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.315

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.0742

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.325

Gnomad OTH

AF:

0.260

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

GnomAD4 genome

AF:

0.253

AC:

38511

AN:

152194

Hom.:

5319

Cov.:

AF XY:

0.248

AC XY:

18449

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.161

AC:

6679

AN:

41518

American (AMR)

AF:

0.223

AC:

3415

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1068

AN:

3470

East Asian (EAS)

AF:

0.0744

AC:

386

AN:

5190

South Asian (SAS)

AF:

0.218

AC:

1052

AN:

4818

European-Finnish (FIN)

AF:

0.275

AC:

2909

AN:

10588

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.325

AC:

22087

AN:

67992

Other (OTH)

AF:

0.262

AC:

554

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1498

2995

4493

5990

7488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.299

Hom.:

29673

Bravo

AF:

0.246

Asia WGS

AF:

0.174

AC:

603

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.0

(source)

DANN

Benign

0.52

PhyloP100

-0.58

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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