5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000675179.1(CAST):​c.2037+3_2037+4delAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 502,162 control chromosomes in the GnomAD database, including 8,837 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (7481 hom., cov: 0)
  • Exomes 𝑓: 0.20 (1356 hom.)
• Consequence: CAST ENST00000675179.1 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 5-96765327-TAA-T is Benign according to our data. Variant chr5-96765327-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 1229222.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.423 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.2037+27_2037+28delAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2101_2819-2100delTT		intron	N/A	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.2819-2101_2819-2100delTT		intron	N/A	NP_057526.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2037+3_2037+4delAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2101_2819-2100delTT		intron	N/A	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000341926.7	TSL:1	c.1788+3_1788+4delAA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.387 AC: 38186 AN: 98706 Hom.: 7484 Cov.: 0

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.365

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.0289 AC: 351 AN: 12164 AF XY: 0.0335

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.0578

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.0477

Gnomad FIN exome AF: 0.00368

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.196 AC: 79237 AN: 403464 Hom.: 1356 AF XY: 0.196 AC XY: 42398 AN XY: 216852

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

African (AFR) AF: 0.141 AC: 1274 AN: 9058

American (AMR) AF: 0.177 AC: 2354 AN: 13314

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 2237 AN: 10846

East Asian (EAS) AF: 0.204 AC: 4610 AN: 22632

South Asian (SAS) AF: 0.181 AC: 5424 AN: 29950

European-Finnish (FIN) AF: 0.174 AC: 5216 AN: 30016

Middle Eastern (MID) AF: 0.209 AC: 348 AN: 1664

European-Non Finnish (NFE) AF: 0.202 AC: 53493 AN: 264588

Other (OTH) AF: 0.200 AC: 4281 AN: 21396

⚠️ 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: 0.387 AC: 38174 AN: 98698 Hom.: 7481 Cov.: 0 AF XY: 0.385 AC XY: 17381 AN XY: 45194

African (AFR) AF: 0.283 AC: 7163 AN: 25280

American (AMR) AF: 0.434 AC: 3941 AN: 9074

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1141 AN: 2730

East Asian (EAS) AF: 0.350 AC: 1185 AN: 3388

South Asian (SAS) AF: 0.381 AC: 1092 AN: 2866

European-Finnish (FIN) AF: 0.436 AC: 1176 AN: 2700

Middle Eastern (MID) AF: 0.367 AC: 61 AN: 166

European-Non Finnish (NFE) AF: 0.428 AC: 21583 AN: 50446

Other (OTH) AF: 0.370 AC: 484 AN: 1308

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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)		0.010		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; COSMIC: COSV57089607; COSMIC: COSV57089607;