chr5-96765060-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
• Publications: 9 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=-0.97).
• BP6: Variant 5-96765060-G-C is Benign according to our data. Variant chr5-96765060-G-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.1933-161G>C		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-1832C>G		intron	N/A	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.2819-1832C>G		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.1933-161G>C		intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-1832C>G		intron	N/A	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000341926.7	TSL:1	c.1684-161G>C		intron	N/A	ENSP00000339914.3

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

African (AFR) AF: 0.423 AC: 17474 AN: 41308

American (AMR) AF: 0.360 AC: 5491 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1799 AN: 3466

East Asian (EAS) AF: 0.123 AC: 630 AN: 5132

South Asian (SAS) AF: 0.469 AC: 2255 AN: 4808

European-Finnish (FIN) AF: 0.385 AC: 4039 AN: 10492

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

European-Non Finnish (NFE) AF: 0.452 AC: 30683 AN: 67876

Other (OTH) AF: 0.402 AC: 846 AN: 2106

Alfa AF: 0.289 Hom.: 672

Bravo AF: 0.417

Asia WGS AF: 0.309 AC: 1074 AN: 3478

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	-0.97
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.10
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: rs26501; hg19: chr5-96100764; COSMIC: COSV57086132; COSMIC: COSV57086132;