5-96765327-T-TAA

Variant names:

• chr5-96765327-T-TAA
• rs59338324
• NM_001750.7:c.2037+27_2037+28dupAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001750.7(CAST):​c.2037+27_2037+28dupAA 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 0.0014 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00141 (139/98892) while in subpopulation AFR AF = 0.00505 (128/25358). AF 95% confidence interval is 0.00434. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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+27_2037+28dupAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2101_2819-2100dupTT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2101_2819-2100dupTT		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+2_2037+3insAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2100_2819-2099insTT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+2_1788+3insAA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 139 AN: 98900 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000346

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00153

GnomAD4 exome AF: 0.000131 AC: 54 AN: 413314 Hom.: 0 Cov.: 0 AF XY: 0.000139 AC XY: 31 AN XY: 222542

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

African (AFR) AF: 0.000539 AC: 5 AN: 9282

American (AMR) AF: 0.0000731 AC: 1 AN: 13674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11088

East Asian (EAS) AF: 0.00 AC: 0 AN: 23216

South Asian (SAS) AF: 0.000454 AC: 14 AN: 30862

European-Finnish (FIN) AF: 0.000131 AC: 4 AN: 30530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1706

European-Non Finnish (NFE) AF: 0.0000812 AC: 22 AN: 270990

Other (OTH) AF: 0.000364 AC: 8 AN: 21966

⚠️ 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 AF: 0.00141 AC: 139 AN: 98892 Hom.: 1 Cov.: 0 AF XY: 0.00141 AC XY: 64 AN XY: 45260

African (AFR) AF: 0.00505 AC: 128 AN: 25358

American (AMR) AF: 0.000550 AC: 5 AN: 9092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2730

East Asian (EAS) AF: 0.00 AC: 0 AN: 3408

South Asian (SAS) AF: 0.000348 AC: 1 AN: 2876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.0000594 AC: 3 AN: 50518

Other (OTH) AF: 0.00152 AC: 2 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

Splicing

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

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;