5-96765327-TAAA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001750.7(CAST):c.2037+26_2037+28del variant causes a splice donor 5th base, 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 splice_donor_5th_base, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.2037+26_2037+28del		splice_donor_5th_base_variant, intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.2037+26_2037+28del		splice_donor_5th_base_variant, intron_variant			NM_001750.7	A2

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

GnomAD3 exomes AF: 0.0261 AC: 317 AN: 12164 Hom.: 21 AF XY: 0.0267 AC XY: 170 AN XY: 6366

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 SAS exome AF: 0.0238

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

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.250

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

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.295

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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)		0.0		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;