Genetic Variant CAST:c.2176-22G>A (chr5-96767885-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.2176-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,534,840 control chromosomes in the GnomAD database, including 2,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.045 ( 189 hom., cov: 32)

Exomes 𝑓: 0.060 ( 2779 hom. )

Consequence

CAST
NM_001750.7 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.210

Publications

8 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 links:

ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

ERAP1 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=-0.82).

BP6

Variant 5-96767885-G-A is Benign according to our data. Variant chr5-96767885-G-A is described in ClinVar as Benign. ClinVar VariationId is 1287686.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0866 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.2176-22G>A	intron	N/A	NP_001741.4
ERAP1	NM_001349244.2		c.2819-4657C>T	intron	N/A	NP_001336173.1	Q9NZ08-2
ERAP1	NM_016442.5		c.2819-4657C>T	intron	N/A	NP_057526.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CAST	ENST00000675179.1	MANE Select	c.2176-22G>A	intron	N/A	ENSP00000501872.1
ERAP1	ENST00000296754.7	TSL:1	c.2819-4657C>T	intron	N/A	ENSP00000296754.3	Q9NZ08-2
CAST	ENST00000341926.7	TSL:1	c.1927-22G>A	intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes

AF:

0.0451

AC:

6864

AN:

152036

Hom.:

188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0187

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0943

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0593

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0536

AC:

13383

AN:

249696

AF XY:

0.0578

show subpopulations

Gnomad AFR exome

AF:

0.0165

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.0440

Gnomad NFE exome

AF:

0.0609

Gnomad OTH exome

AF:

0.0554

GnomAD4 exome

AF:

0.0595

AC:

82310

AN:

1382686

Hom.:

2779

Cov.:

AF XY:

0.0613

AC XY:

42422

AN XY:

692168

show subpopulations

African (AFR)

AF:

0.0158

AC:

504

AN:

31884

American (AMR)

AF:

0.0302

AC:

1338

AN:

44236

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2727

AN:

25658

East Asian (EAS)

AF:

0.000280

AC:

AN:

39296

South Asian (SAS)

AF:

0.0953

AC:

8053

AN:

84484

European-Finnish (FIN)

AF:

0.0448

AC:

2392

AN:

53344

Middle Eastern (MID)

AF:

0.0938

AC:

524

AN:

5586

European-Non Finnish (NFE)

AF:

0.0610

AC:

63451

AN:

1040536

Other (OTH)

AF:

0.0574

AC:

3310

AN:

57662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3719

7439

11158

14878

18597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2298

4596

6894

9192

11490

<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:

0.0451

AC:

6859

AN:

152154

Hom.:

189

Cov.:

AF XY:

0.0445

AC XY:

3313

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0186

AC:

771

AN:

41498

American (AMR)

AF:

0.0395

AC:

603

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

394

AN:

3468

East Asian (EAS)

AF:

0.000964

AC:

AN:

5186

South Asian (SAS)

AF:

0.0938

AC:

452

AN:

4820

European-Finnish (FIN)

AF:

0.0440

AC:

466

AN:

10580

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0593

AC:

4031

AN:

68008

Other (OTH)

AF:

0.0440

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

336

672

1008

1344

1680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0610

Hom.:

Bravo

AF:

0.0423

Asia WGS

AF:

0.0300

AC:

106

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

-0.82

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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