5-96765060-G-C

Variant names:

• chr5-96765060-G-C
• rs26501
• NM_001750.7:c.1933-161G>C

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.1933-161G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 151,636 control chromosomes in the GnomAD database, including 13,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.42 (13755 hom., cov: 30)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.102

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 5-96765060-G-C is Benign according to our data. Variant chr5-96765060-G-C is described in ClinVar as [Benign]. Clinvar id is 1222451.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1933-161G>C		intron_variant	Intron 25 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1933-161G>C		intron_variant	Intron 25 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63738 AN: 151518 Hom.: 13739 Cov.: 30

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.402

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

GnomAD4 genome AF: 0.421 AC: 63796 AN: 151636 Hom.: 13755 Cov.: 30 AF XY: 0.416 AC XY: 30795 AN XY: 74062

Gnomad4 AFR AF: 0.423 AC: 0.423017 AN: 0.423017

Gnomad4 AMR AF: 0.360 AC: 0.36016 AN: 0.36016

Gnomad4 ASJ AF: 0.519 AC: 0.519042 AN: 0.519042

Gnomad4 EAS AF: 0.123 AC: 0.122759 AN: 0.122759

Gnomad4 SAS AF: 0.469 AC: 0.46901 AN: 0.46901

Gnomad4 FIN AF: 0.385 AC: 0.38496 AN: 0.38496

Gnomad4 NFE AF: 0.452 AC: 0.452045 AN: 0.452045

Gnomad4 OTH AF: 0.402 AC: 0.401709 AN: 0.401709

Alfa AF: 0.289 Hom.: 672

Bravo AF: 0.417

Asia WGS AF: 0.309 AC: 1074 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.6
DANN	Benign	0.66
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

Publications

LitVar

Other links and lift over

dbSNP: rs26501; hg19: chr5-96100764; COSMIC: COSV57086132; COSMIC: COSV57086132;