5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAAAA

Variant names:

• chr5-96765327-TAAAA-T
• rs59338324
• NM_001750.7:c.2037+25_2037+28delAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001750.7(CAST):​c.2037+25_2037+28delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 403,158 control chromosomes in the GnomAD database, including 729 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0080 (21 hom., cov: 0)
  • Exomes 𝑓: 0.18 (729 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 1 publications found

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]

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]

CAST (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 729 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.2037+25_2037+28delAAAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2103_2819-2100delTTTT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2103_2819-2100delTTTT		intron	N/A	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2037+3_2037+6delAAAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2103_2819-2100delTTTT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+3_1788+6delAAAA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 791 AN: 98898 Hom.: 21 Cov.: 0

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.000366

Gnomad EAS AF: 0.0228

Gnomad SAS AF: 0.00346

Gnomad FIN AF: 0.00371

Gnomad MID AF: 0.00595

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0323 AC: 393 AN: 12164 AF XY: 0.0366

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0493

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.0618

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.175 AC: 70648 AN: 403158 Hom.: 729 AF XY: 0.175 AC XY: 37942 AN XY: 216696

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

African (AFR) AF: 0.186 AC: 1699 AN: 9116

American (AMR) AF: 0.197 AC: 2628 AN: 13364

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 1857 AN: 10826

East Asian (EAS) AF: 0.182 AC: 4089 AN: 22516

South Asian (SAS) AF: 0.177 AC: 5327 AN: 30148

European-Finnish (FIN) AF: 0.141 AC: 4209 AN: 29798

Middle Eastern (MID) AF: 0.185 AC: 308 AN: 1668

European-Non Finnish (NFE) AF: 0.176 AC: 46564 AN: 264346

Other (OTH) AF: 0.186 AC: 3967 AN: 21376

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00803 AC: 794 AN: 98890 Hom.: 21 Cov.: 0 AF XY: 0.00893 AC XY: 404 AN XY: 45260

African (AFR) AF: 0.0114 AC: 288 AN: 25356

American (AMR) AF: 0.0344 AC: 313 AN: 9096

Ashkenazi Jewish (ASJ) AF: 0.000366 AC: 1 AN: 2730

East Asian (EAS) AF: 0.0226 AC: 77 AN: 3406

South Asian (SAS) AF: 0.00348 AC: 10 AN: 2876

European-Finnish (FIN) AF: 0.00371 AC: 10 AN: 2698

Middle Eastern (MID) AF: 0.00610 AC: 1 AN: 164

European-Non Finnish (NFE) AF: 0.00156 AC: 79 AN: 50516

Other (OTH) AF: 0.0114 AC: 15 AN: 1312

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;