5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAA

Variant names:

• chr5-96765327-TAAAAAAA-T
• rs59338324
• NM_001750.7:c.2037+22_2037+28delAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000675179.1(CAST):​c.2037+3_2037+9delAAAAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 510,242 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0048 (1 hom.)
• Consequence: CAST ENST00000675179.1 splice_region, 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675179.1. 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+22_2037+28delAAAAAAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2106_2819-2100delTTTTTTT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2106_2819-2100delTTTTTTT		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+9delAAAAAAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2106_2819-2100delTTTTTTT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+3_1788+9delAAAAAAA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.0000708 AC: 7 AN: 98900 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000767

GnomAD4 exome AF: 0.00480 AC: 1976 AN: 411342 Hom.: 1 AF XY: 0.00479 AC XY: 1061 AN XY: 221506

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

African (AFR) AF: 0.00541 AC: 50 AN: 9238

American (AMR) AF: 0.0101 AC: 137 AN: 13554

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 57 AN: 11026

East Asian (EAS) AF: 0.00373 AC: 86 AN: 23080

South Asian (SAS) AF: 0.00573 AC: 176 AN: 30742

European-Finnish (FIN) AF: 0.00342 AC: 104 AN: 30406

Middle Eastern (MID) AF: 0.00413 AC: 7 AN: 1696

European-Non Finnish (NFE) AF: 0.00466 AC: 1258 AN: 269742

Other (OTH) AF: 0.00462 AC: 101 AN: 21858

⚠️ 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: 0.0000708 AC: 7 AN: 98900 Hom.: 0 Cov.: 0 AF XY: 0.000110 AC XY: 5 AN XY: 45250

African (AFR) AF: 0.000197 AC: 5 AN: 25330

American (AMR) AF: 0.00 AC: 0 AN: 9086

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3424

South Asian (SAS) AF: 0.000346 AC: 1 AN: 2892

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 168

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50532

Other (OTH) AF: 0.000767 AC: 1 AN: 1304

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		=98/2	polymorphism

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;