5-96766240-A-G

Position:

• chr5-96766240-A-G

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.2130+95A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 710,624 control chromosomes in the GnomAD database, including 143,368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (29106 hom., cov: 32)
  • Exomes 𝑓: 0.64 (114262 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.71

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-96766240-A-G is Benign according to our data. Variant chr5-96766240-A-G is described in ClinVar as [Benign]. Clinvar id is 1278838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.2130+95A>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.2130+95A>G		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93573 AN: 151940 Hom.: 29069 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.637 AC: 355607 AN: 558566 Hom.: 114262 AF XY: 0.633 AC XY: 189562 AN XY: 299352

Gnomad4 AFR exome AF: 0.567

Gnomad4 AMR exome AF: 0.764

Gnomad4 ASJ exome AF: 0.559

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.596

Gnomad4 FIN exome AF: 0.660

Gnomad4 NFE exome AF: 0.636

Gnomad4 OTH exome AF: 0.617

GnomAD4 genome AF: 0.616 AC: 93671 AN: 152058 Hom.: 29106 Cov.: 32 AF XY: 0.617 AC XY: 45876 AN XY: 74330

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.693

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.604

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.658

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.580

Alfa AF: 0.625 Hom.: 49570

Bravo AF: 0.616

Asia WGS AF: 0.635 AC: 2207 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 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs27524; hg19: chr5-96101944;