5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAA

Variant names:

• chr5-96765327-TAAAAAA-T
• rs59338324
• NM_001750.7:c.2037+23_2037+28delAAAAAA

Variant summary

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

• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

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+23_2037+28delAAAAAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2105_2819-2100delTTTTTT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2105_2819-2100delTTTTTT		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+8delAAAAAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2105_2819-2100delTTTTTT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+3_1788+8delAAAAAA		splice_region intron	N/A	ENSP00000339914.3

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

GnomAD2 exomes AF: 0.0173 AC: 210 AN: 12164 AF XY: 0.0189

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 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

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

African (AFR) AF: 0.0240 AC: 220 AN: 9162

American (AMR) AF: 0.0330 AC: 443 AN: 13428

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 220 AN: 10958

East Asian (EAS) AF: 0.0169 AC: 386 AN: 22844

South Asian (SAS) AF: 0.0226 AC: 690 AN: 30578

European-Finnish (FIN) AF: 0.0149 AC: 450 AN: 30196

Middle Eastern (MID) AF: 0.0243 AC: 41 AN: 1690

European-Non Finnish (NFE) AF: 0.0201 AC: 5375 AN: 267494

Other (OTH) AF: 0.0209 AC: 452 AN: 21672

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

African (AFR) AF: 0.00 AC: 0 AN: 25358

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.0000198 AC: 1 AN: 50518

Other (OTH) AF: 0.00 AC: 0 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

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

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;