5-96765327-TAA-T

Position:

• chr5-96765327-TAA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001750.7(CAST):​c.2037+27_2037+28del variant causes a splice donor 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. 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 NM_001750.7 splice_donor_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.47

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.2037+27_2037+28del		splice_donor_region_variant, intron_variant		ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.2037+27_2037+28del		splice_donor_region_variant, intron_variant			NM_001750.7	ENSP00000501872	A2

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

GnomAD3 exomes AF: 0.0289 AC: 351 AN: 12164 Hom.: 17 AF XY: 0.0335 AC XY: 213 AN XY: 6366

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 SAS exome AF: 0.102

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

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.387 AC: 38174 AN: 98698 Hom.: 7481 Cov.: 0 AF XY: 0.385 AC XY: 17381 AN XY: 45194

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.434

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.370

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;