5-96765516-A-G

Position:

• chr5-96765516-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.2037+191A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 151,806 control chromosomes in the GnomAD database, including 4,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4718 hom., cov: 31)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.546

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=-0.94).
• BP6: Variant 5-96765516-A-G is Benign according to our data. Variant chr5-96765516-A-G is described in ClinVar as [Benign]. Clinvar id is 1261787.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.2037+191A>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.2037+191A>G		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35552 AN: 151686 Hom.: 4714 Cov.: 31

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.0787

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.221

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35566 AN: 151806 Hom.: 4718 Cov.: 31 AF XY: 0.231 AC XY: 17112 AN XY: 74168

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.0791

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.221

Alfa AF: 0.271 Hom.: 730

Bravo AF: 0.222

Asia WGS AF: 0.161 AC: 560 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	-0.94
CADD	Benign	0.22
DANN	Benign	0.39

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: rs28580505; hg19: chr5-96101220;