5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAA

Variant names:

• chr5-96765327-T-TA
• rs59338324
• NM_001750.7:c.2037+28dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000675179.1(CAST):​c.2037+2_2037+3insA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (0 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00369 (365/98890) while in subpopulation AFR AF = 0.0103 (261/25356). AF 95% confidence interval is 0.00927. There are 6 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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+28dupA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2100dupT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2100dupT		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+3insA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2100_2819-2099insT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+2_1788+3insA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 364 AN: 98898 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00321

Gnomad SAS AF: 0.00623

Gnomad FIN AF: 0.000371

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00230

GnomAD4 exome AF: 0.00121 AC: 501 AN: 413038 Hom.: 0 Cov.: 0 AF XY: 0.00124 AC XY: 276 AN XY: 222390

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

African (AFR) AF: 0.00334 AC: 31 AN: 9276

American (AMR) AF: 0.000658 AC: 9 AN: 13668

Ashkenazi Jewish (ASJ) AF: 0.00163 AC: 18 AN: 11074

East Asian (EAS) AF: 0.00246 AC: 57 AN: 23188

South Asian (SAS) AF: 0.00305 AC: 94 AN: 30840

European-Finnish (FIN) AF: 0.000852 AC: 26 AN: 30514

Middle Eastern (MID) AF: 0.00118 AC: 2 AN: 1700

European-Non Finnish (NFE) AF: 0.000857 AC: 232 AN: 270826

Other (OTH) AF: 0.00146 AC: 32 AN: 21952

⚠️ 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: 0.00369 AC: 365 AN: 98890 Hom.: 6 Cov.: 0 AF XY: 0.00371 AC XY: 168 AN XY: 45256

African (AFR) AF: 0.0103 AC: 261 AN: 25356

American (AMR) AF: 0.00187 AC: 17 AN: 9092

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

East Asian (EAS) AF: 0.00323 AC: 11 AN: 3408

South Asian (SAS) AF: 0.00661 AC: 19 AN: 2874

European-Finnish (FIN) AF: 0.000371 AC: 1 AN: 2698

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

European-Non Finnish (NFE) AF: 0.00105 AC: 53 AN: 50520

Other (OTH) AF: 0.00229 AC: 3 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
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;