rs25862

chr5-96769131-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001750.7(CAST):c.2268+1132G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 151,998 control chromosomes in the GnomAD database, including 13,868 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (13867 hom., cov: 32)
  • Exomes 𝑓: 0.44 (1 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.2268+1132G>A		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.2268+1132G>A		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64016 AN: 151864 Hom.: 13854 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.438 AC: 7 AN: 16 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 7 AN XY: 14

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.429

GnomAD4 genome AF: 0.422 AC: 64066 AN: 151982 Hom.: 13867 Cov.: 32 AF XY: 0.417 AC XY: 30968 AN XY: 74268

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.402

Alfa AF: 0.446 Hom.: 30870

Bravo AF: 0.418

Asia WGS AF: 0.314 AC: 1093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.8
Dann	Benign	0.73

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: rs25862; hg19: chr5-96104835;