Genetic Variant CAST:c.2037+25_2037+28dupAAAA (chr5-96765327-T-TAAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001750.7(CAST):c.2037+25_2037+28dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAST
NM_001750.7 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.47

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2037+25_2037+28dupAAAA	intron	N/A	NP_001741.4
ERAP1	NM_001349244.2		c.2819-2103_2819-2100dupTTTT	intron	N/A	NP_001336173.1
ERAP1	NM_016442.5		c.2819-2103_2819-2100dupTTTT	intron	N/A	NP_057526.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.2037+2_2037+3insAAAA	splice_region intron	N/A	ENSP00000501872.1
ERAP1	ENST00000296754.7	TSL:1	c.2819-2100_2819-2099insTTTT	intron	N/A	ENSP00000296754.3
CAST	ENST00000341926.7	TSL:1	c.1788+2_1788+3insAAAA	splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

98902

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

413386

Hom.:

Cov.:

AF XY:

0.00000449

AC XY:

AN XY:

222582

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000108

AC:

AN:

9286

American (AMR)

AF:

0.00

AC:

AN:

13674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11092

East Asian (EAS)

AF:

0.0000431

AC:

AN:

23220

South Asian (SAS)

AF:

0.00

AC:

AN:

30868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

271034

Other (OTH)

AF:

0.00

AC:

AN:

21970

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

98902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

45250

African (AFR)

AF:

0.00

AC:

AN:

25330

American (AMR)

AF:

0.00

AC:

AN:

9086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2730

East Asian (EAS)

AF:

0.00

AC:

AN:

3424

South Asian (SAS)

AF:

0.00

AC:

AN:

2892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

50534

Other (OTH)

AF:

0.00

AC:

AN:

1304

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Splicing

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

Publications

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5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAA

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