5-96766240-A-G

Variant names:

• chr5-96766240-A-G
• rs27524
• NM_001750.7:c.2130+95A>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.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
• Publications: 92 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=-0.9).
• BP6: Variant 5-96766240-A-G is Benign according to our data. Variant chr5-96766240-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.2130+95A>G		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-3012T>C		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-3012T>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.2130+95A>G		intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-3012T>C		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1881+95A>G		intron	N/A	ENSP00000339914.3

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

African (AFR) AF: 0.567 AC: 8065 AN: 14232

American (AMR) AF: 0.764 AC: 21387 AN: 27988

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 8892 AN: 15898

East Asian (EAS) AF: 0.661 AC: 21799 AN: 32988

South Asian (SAS) AF: 0.596 AC: 31877 AN: 53500

European-Finnish (FIN) AF: 0.660 AC: 30751 AN: 46558

Middle Eastern (MID) AF: 0.597 AC: 2264 AN: 3792

European-Non Finnish (NFE) AF: 0.636 AC: 212257 AN: 333950

Other (OTH) AF: 0.617 AC: 18315 AN: 29660

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

African (AFR) AF: 0.561 AC: 23239 AN: 41452

American (AMR) AF: 0.693 AC: 10581 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1955 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3129 AN: 5178

South Asian (SAS) AF: 0.594 AC: 2861 AN: 4814

European-Finnish (FIN) AF: 0.658 AC: 6954 AN: 10574

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43188 AN: 67980

Other (OTH) AF: 0.580 AC: 1224 AN: 2110

Alfa AF: 0.627 Hom.: 117356

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

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.36
PhyloP100		-1.7
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs27524; hg19: chr5-96101944;