NM_001750.7:c.2037+26_2037+28delAAA

Variant names:

• chr5-96765327-TAAA-T
• rs59338324
• NM_001750.7:c.2037+26_2037+28delAAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001750.7(CAST):​c.2037+26_2037+28delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 408,304 control chromosomes in the GnomAD database, including 2,401 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (4884 hom., cov: 0)
  • Exomes 𝑓: 0.25 (2401 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 5-96765327-TAAA-T is Benign according to our data. Variant chr5-96765327-TAAA-T is described in ClinVar as Benign. ClinVar VariationId is 402496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

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+26_2037+28delAAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2102_2819-2100delTTT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2102_2819-2100delTTT		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+5delAAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2102_2819-2100delTTT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+3_1788+5delAAA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.312 AC: 30823 AN: 98812 Hom.: 4879 Cov.: 0

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.0261 AC: 317 AN: 12164 AF XY: 0.0267

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0510

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.0565

Gnomad FIN exome AF: 0.00501

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0579

GnomAD4 exome AF: 0.249 AC: 101554 AN: 408304 Hom.: 2401 AF XY: 0.248 AC XY: 54389 AN XY: 219672

African (AFR) AF: 0.261 AC: 2391 AN: 9178

American (AMR) AF: 0.236 AC: 3201 AN: 13538

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 2563 AN: 10962

East Asian (EAS) AF: 0.257 AC: 5872 AN: 22832

South Asian (SAS) AF: 0.223 AC: 6799 AN: 30448

European-Finnish (FIN) AF: 0.204 AC: 6165 AN: 30202

Middle Eastern (MID) AF: 0.268 AC: 450 AN: 1678

European-Non Finnish (NFE) AF: 0.257 AC: 68709 AN: 267808

Other (OTH) AF: 0.250 AC: 5404 AN: 21658

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.312 AC: 30825 AN: 98804 Hom.: 4884 Cov.: 0 AF XY: 0.315 AC XY: 14232 AN XY: 45202

African (AFR) AF: 0.396 AC: 9997 AN: 25274

American (AMR) AF: 0.298 AC: 2716 AN: 9100

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 777 AN: 2722

East Asian (EAS) AF: 0.296 AC: 1005 AN: 3400

South Asian (SAS) AF: 0.345 AC: 989 AN: 2870

European-Finnish (FIN) AF: 0.276 AC: 747 AN: 2702

Middle Eastern (MID) AF: 0.287 AC: 47 AN: 164

European-Non Finnish (NFE) AF: 0.277 AC: 13978 AN: 50522

Other (OTH) AF: 0.295 AC: 387 AN: 1312

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (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)		0.0		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;