dbSNP rs26503: CAST:c.1099-50G>A (chr5-96742605-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001750.7(CAST):c.1099-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,107,250 control chromosomes in the GnomAD database, including 283,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.68 ( 35610 hom., cov: 31)

Exomes 𝑓: 0.72 ( 248292 hom. )

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.155

Publications

16 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, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 5-96742605-G-A is Benign according to our data. Variant chr5-96742605-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241904.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.759 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	UniProt
CAST	NM_001750.7	MANE Select	c.1099-50G>A	intron	N/A	NP_001741.4
CAST	NM_001042441.3		c.1042-50G>A	intron	N/A	NP_001035906.1	P20810-7
CAST	NM_001042442.3		c.1033-50G>A	intron	N/A	NP_001035907.1	P20810-10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.1099-50G>A	intron	N/A	ENSP00000501872.1
CAST	ENST00000341926.7	TSL:1	c.850-50G>A	intron	N/A	ENSP00000339914.3
CAST	ENST00000338252.7	TSL:1	c.811-50G>A	intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes

AF:

0.681

AC:

103358

AN:

151852

Hom.:

35578

Cov.:

show subpopulations

Gnomad AFR

AF:

0.569

Gnomad AMI

AF:

0.643

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.643

Gnomad SAS

AF:

0.641

Gnomad FIN

AF:

0.732

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.731

Gnomad OTH

AF:

0.675

GnomAD2 exomes

AF:

0.713

AC:

163908

AN:

229862

AF XY:

0.709

show subpopulations

Gnomad AFR exome

AF:

0.567

Gnomad AMR exome

AF:

0.843

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.623

Gnomad FIN exome

AF:

0.734

Gnomad NFE exome

AF:

0.733

Gnomad OTH exome

AF:

0.716

GnomAD4 exome

AF:

0.718

AC:

685775

AN:

955280

Hom.:

248292

Cov.:

AF XY:

0.716

AC XY:

354812

AN XY:

495824

show subpopulations

African (AFR)

AF:

0.556

AC:

13121

AN:

23614

American (AMR)

AF:

0.837

AC:

35583

AN:

42534

Ashkenazi Jewish (ASJ)

AF:

0.605

AC:

13801

AN:

22810

East Asian (EAS)

AF:

0.686

AC:

25233

AN:

36782

South Asian (SAS)

AF:

0.635

AC:

47499

AN:

74796

European-Finnish (FIN)

AF:

0.734

AC:

38517

AN:

52456

Middle Eastern (MID)

AF:

0.594

AC:

2866

AN:

4826

European-Non Finnish (NFE)

AF:

0.733

AC:

478983

AN:

653876

Other (OTH)

AF:

0.692

AC:

30172

AN:

43586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

9482

18965

28447

37930

47412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8892

17784

26676

35568

44460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.681

AC:

103434

AN:

151970

Hom.:

35610

Cov.:

AF XY:

0.682

AC XY:

50608

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.569

AC:

23586

AN:

41420

American (AMR)

AF:

0.771

AC:

11772

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2082

AN:

3470

East Asian (EAS)

AF:

0.643

AC:

3320

AN:

5162

South Asian (SAS)

AF:

0.641

AC:

3078

AN:

4802

European-Finnish (FIN)

AF:

0.732

AC:

7729

AN:

10556

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.731

AC:

49668

AN:

67972

Other (OTH)

AF:

0.676

AC:

1423

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1658

3317

4975

6634

8292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.700

Hom.:

17711

Bravo

AF:

0.680

Asia WGS

AF:

0.663

AC:

2309

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.4

(source)

DANN

Benign

0.87

PhyloP100

-0.15

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over