rs27765

Positions:

• chr5-96767885-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):​c.2176-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,534,840 control chromosomes in the GnomAD database, including 2,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (189 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2779 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.210

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-96767885-G-A is Benign according to our data. Variant chr5-96767885-G-A is described in ClinVar as [Benign]. Clinvar id is 1287686.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.2176-22G>A		intron_variant		ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.2176-22G>A		intron_variant			NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6864 AN: 152036 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0943

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0536 AC: 13383 AN: 249696 Hom.: 469 AF XY: 0.0578 AC XY: 7804 AN XY: 134986

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.0938

Gnomad FIN exome AF: 0.0440

Gnomad NFE exome AF: 0.0609

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0595 AC: 82310 AN: 1382686 Hom.: 2779 Cov.: 23 AF XY: 0.0613 AC XY: 42422 AN XY: 692168

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.0953

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0610

Gnomad4 OTH exome AF: 0.0574

GnomAD4 genome AF: 0.0451 AC: 6859 AN: 152154 Hom.: 189 Cov.: 32 AF XY: 0.0445 AC XY: 3313 AN XY: 74378

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.0395

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0938

Gnomad4 FIN AF: 0.0440

Gnomad4 NFE AF: 0.0593

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0616 Hom.: 58

Bravo AF: 0.0423

Asia WGS AF: 0.0300 AC: 106 AN: 3478

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

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs27765; hg19: chr5-96103589;