chr5-96765327-TAAAA-T

Position:

• chr5-96765327-TAAAA-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

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

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

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.2037+25_2037+28delAAAA		intron_variant		ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.2037+25_2037+28delAAAA		intron_variant			NM_001750.7	ENSP00000501872.1

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

GnomAD3 exomes AF: 0.0323 AC: 393 AN: 12164 Hom.: 18 AF XY: 0.0366 AC XY: 233 AN XY: 6366

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 SAS exome AF: 0.0165

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

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.186

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

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0344

Gnomad4 ASJ AF: 0.000366

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.00348

Gnomad4 FIN AF: 0.00371

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.0114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;