NM_001750.7:c.2037+191A>G

Variant names:

• chr5-96765516-A-G
• rs28580505
• NM_001750.7:c.2037+191A>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.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
• Publications: 5 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=-0.94).
• BP6: Variant 5-96765516-A-G is Benign according to our data. Variant chr5-96765516-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.2037+191A>G		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2288T>C		intron	N/A	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.2819-2288T>C		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.2037+191A>G		intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2288T>C		intron	N/A	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000341926.7	TSL:1	c.1788+191A>G		intron	N/A	ENSP00000339914.3

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

African (AFR) AF: 0.112 AC: 4633 AN: 41458

American (AMR) AF: 0.211 AC: 3215 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 917 AN: 3462

East Asian (EAS) AF: 0.0791 AC: 409 AN: 5170

South Asian (SAS) AF: 0.213 AC: 1028 AN: 4816

European-Finnish (FIN) AF: 0.295 AC: 3094 AN: 10488

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.318 AC: 21547 AN: 67854

Other (OTH) AF: 0.221 AC: 466 AN: 2112

Alfa AF: 0.265 Hom.: 734

Bravo AF: 0.222

Asia WGS AF: 0.161 AC: 560 AN: 3478

ClinVar

ClinVar submissions

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	-0.94
CADD	Benign	0.22
DANN	Benign	0.39
PhyloP100		-0.55
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: rs28580505; hg19: chr5-96101220;