rs28096

Positions:

• chr5-96773540-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.*924G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,902 control chromosomes in the GnomAD database, including 7,738 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 0.31 (7732 hom., cov: 31)
  • Exomes 𝑓: 0.29 (6 hom.)
• Consequence: CAST NM_001750.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163

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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.*924G>A		3_prime_UTR_variant	32/32	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.*924G>A		3_prime_UTR_variant	32/32		NM_001750.7	ENSP00000501872	A2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47132 AN: 151644 Hom.: 7728 Cov.: 31

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.286 AC: 40 AN: 140 Hom.: 6 Cov.: 0 AF XY: 0.308 AC XY: 24 AN XY: 78

Gnomad4 EAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.311 AC: 47162 AN: 151762 Hom.: 7732 Cov.: 31 AF XY: 0.306 AC XY: 22676 AN XY: 74150

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.266

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.0635

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.289

Alfa AF: 0.360 Hom.: 13214

Bravo AF: 0.302

Asia WGS AF: 0.206 AC: 713 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.57

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: rs28096; hg19: chr5-96109244; COSMIC: COSV57086302; COSMIC: COSV57086302;