chr5-96765327-TA-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000675179.1(CAST):​c.2037+3delA 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 0.13 (892 hom., cov: 0)
  • Exomes 𝑓: 0.063 (101 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.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

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+28delA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2100delT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2100delT		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+3delA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2100delT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+3delA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 12440 AN: 98640 Hom.: 892 Cov.: 0

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00643

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.00871 AC: 106 AN: 12164 AF XY: 0.00770

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.00971

Gnomad EAS exome AF: 0.0424

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0631 AC: 25370 AN: 401916 Hom.: 101 Cov.: 0 AF XY: 0.0633 AC XY: 13661 AN XY: 215946

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

African (AFR) AF: 0.0531 AC: 481 AN: 9066

American (AMR) AF: 0.0479 AC: 639 AN: 13332

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 742 AN: 10778

East Asian (EAS) AF: 0.0546 AC: 1237 AN: 22652

South Asian (SAS) AF: 0.0496 AC: 1493 AN: 30086

European-Finnish (FIN) AF: 0.0602 AC: 1799 AN: 29892

Middle Eastern (MID) AF: 0.0557 AC: 91 AN: 1634

European-Non Finnish (NFE) AF: 0.0661 AC: 17389 AN: 263216

Other (OTH) AF: 0.0705 AC: 1499 AN: 21260

⚠️ 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: 0.126 AC: 12437 AN: 98632 Hom.: 892 Cov.: 0 AF XY: 0.122 AC XY: 5509 AN XY: 45130

African (AFR) AF: 0.0585 AC: 1481 AN: 25322

American (AMR) AF: 0.119 AC: 1080 AN: 9076

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 361 AN: 2720

East Asian (EAS) AF: 0.00646 AC: 22 AN: 3406

South Asian (SAS) AF: 0.0904 AC: 259 AN: 2864

European-Finnish (FIN) AF: 0.148 AC: 398 AN: 2688

Middle Eastern (MID) AF: 0.195 AC: 32 AN: 164

European-Non Finnish (NFE) AF: 0.168 AC: 8481 AN: 50350

Other (OTH) AF: 0.147 AC: 192 AN: 1310

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 (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;