5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAA

Position:

• chr5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001750.7(CAST):​c.2037+23_2037+28delAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 506,914 control chromosomes in the GnomAD database, including 15 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.020 (15 hom.)
• 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.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0203 (8277/408022) while in subpopulation AMR AF= 0.033 (443/13428). AF 95% confidence interval is 0.0305. There are 15 homozygotes in gnomad4_exome. There are 4458 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.2037+23_2037+28delAAAAAA		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+23_2037+28delAAAAAA		intron_variant			NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.0000101 AC: 1 AN: 98900 Hom.: 0 Cov.: 0

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: 0.0000198

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0173 AC: 210 AN: 12164 Hom.: 5 AF XY: 0.0189 AC XY: 120 AN XY: 6366

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.00243

Gnomad EAS exome AF: 0.0159

Gnomad SAS exome AF: 0.00517

Gnomad FIN exome AF: 0.00201

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0203 AC: 8277 AN: 408022 Hom.: 15 AF XY: 0.0203 AC XY: 4458 AN XY: 219562

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.0169

Gnomad4 SAS exome AF: 0.0226

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0000101 AC: 1 AN: 98892 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 45258

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000198

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;