NM_001750.7:c.2037+20_2037+28delAAAAAAAAA

Variant names:

• chr5-96765327-TAAAAAAAAA-T
• rs59338324
• NM_001750.7:c.2037+20_2037+28delAAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_001750.7(CAST):​c.2037+20_2037+28delAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 512,116 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00020 (0 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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000196 (81/413214) while in subpopulation AMR AF= 0.000732 (10/13660). AF 95% confidence interval is 0.000397. There are 0 homozygotes in gnomad4_exome. There are 42 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.2037+20_2037+28delAAAAAAAAA		intron_variant	Intron 26 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.2037+3_2037+11delAAAAAAAAA		splice_region_variant, intron_variant	Intron 26 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.0000506 AC: 5 AN: 98902 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000110

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000292

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000396

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000196 AC: 81 AN: 413214 Hom.: 0 AF XY: 0.000189 AC XY: 42 AN XY: 222488

Gnomad4 AFR exome AF: 0.000431

Gnomad4 AMR exome AF: 0.000732

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000172

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.000228

GnomAD4 genome AF: 0.0000506 AC: 5 AN: 98902 Hom.: 0 Cov.: 0 AF XY: 0.0000442 AC XY: 2 AN XY: 45250

Gnomad4 AFR AF: 0.0000395

Gnomad4 AMR AF: 0.000110

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000292

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000396

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;