Genetic Variant NM_001750.7:c.2037+26_2037+28delAAA (chr5-96765327-TAAA-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

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

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.47

Variant links:

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]

CAST links:

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]

ERAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CAST	NM_001750.7 link	c.2037+26_2037+28delAAA		intron_variant	Intron 26 of 31	ENST00000675179.1	NP_001741.4	P20810-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1 link	c.2037+3_2037+5delAAA		splice_region_variant, intron_variant	Intron 26 of 31		NM_001750.7	ENSP00000501872.1		P20810-6

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

30823

AN:

98812

Hom.:

4879

Cov.:

show subpopulations

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.:

AF XY:

0.0267

AC XY:

170

AN XY:

6366

show subpopulations

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

show subpopulations

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.:

AF XY:

0.315

AC XY:

14232

AN XY:

45202

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over