rs25862

Variant names:

• chr5-96769131-G-A
• rs25862
• NM_001750.7:c.2268+1132G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.2268+1132G>A		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-5903C>T		intron	N/A	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.2819-5903C>T		intron	N/A	NP_057526.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2268+1132G>A		intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-5903C>T		intron	N/A	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000341926.7	TSL:1	c.2019+1132G>A		intron	N/A	ENSP00000339914.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.429 AC: 6 AN: 14

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.427 AC: 17695 AN: 41434

American (AMR) AF: 0.362 AC: 5522 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1804 AN: 3472

East Asian (EAS) AF: 0.122 AC: 633 AN: 5176

South Asian (SAS) AF: 0.469 AC: 2260 AN: 4822

European-Finnish (FIN) AF: 0.384 AC: 4039 AN: 10528

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30683 AN: 67956

Other (OTH) AF: 0.402 AC: 851 AN: 2116

Alfa AF: 0.440 Hom.: 64007

Bravo AF: 0.418

Asia WGS AF: 0.314 AC: 1093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.73
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs25862; hg19: chr5-96104835;