rs3214019

Variant names:

• chr5-96767406-A-G
• rs3214019
• NM_001750.7:c.2131-32A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):​c.2131-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 1,581,824 control chromosomes in the GnomAD database, including 5,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (850 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4990 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-96767406-A-G is Benign according to our data. Variant chr5-96767406-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286868.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.2131-32A>G		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-4178T>C		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-4178T>C		intron	N/A	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2131-32A>G		intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-4178T>C		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1882-32A>G		intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14633 AN: 152158 Hom.: 851 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0788 AC: 19699 AN: 250078 AF XY: 0.0812

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0508

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0144

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0891

GnomAD4 exome AF: 0.0780 AC: 111451 AN: 1429548 Hom.: 4990 Cov.: 26 AF XY: 0.0799 AC XY: 57009 AN XY: 713530

African (AFR) AF: 0.159 AC: 5218 AN: 32724

American (AMR) AF: 0.0531 AC: 2364 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3678 AN: 25866

East Asian (EAS) AF: 0.0418 AC: 1650 AN: 39476

South Asian (SAS) AF: 0.135 AC: 11577 AN: 85510

European-Finnish (FIN) AF: 0.0435 AC: 2314 AN: 53196

Middle Eastern (MID) AF: 0.130 AC: 739 AN: 5698

European-Non Finnish (NFE) AF: 0.0726 AC: 78674 AN: 1083352

Other (OTH) AF: 0.0884 AC: 5237 AN: 59246

GnomAD4 genome AF: 0.0962 AC: 14643 AN: 152276 Hom.: 850 Cov.: 32 AF XY: 0.0960 AC XY: 7152 AN XY: 74464

African (AFR) AF: 0.153 AC: 6357 AN: 41540

American (AMR) AF: 0.0709 AC: 1085 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3470

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5186

South Asian (SAS) AF: 0.135 AC: 652 AN: 4822

European-Finnish (FIN) AF: 0.0409 AC: 435 AN: 10630

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0734 AC: 4992 AN: 68014

Other (OTH) AF: 0.104 AC: 219 AN: 2112

Alfa AF: 0.0995 Hom.: 220

Bravo AF: 0.0999

Asia WGS AF: 0.0880 AC: 305 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.61
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3214019; hg19: chr5-96103110;