5-96765340-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001750.7(CAST):c.2037+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 74,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (81 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.966

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=-0.83).
• BP6: Variant 5-96765340-A-G is Benign according to our data. Variant chr5-96765340-A-G is described in ClinVar as [Benign]. Clinvar id is 1631442.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00215 (160/74254) while in subpopulation SAS AF= 0.0294 (63/2142). AF 95% confidence interval is 0.0236. There are 1 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.2037+15A>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.2037+15A>G		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 160 AN: 74204 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

Gnomad ASJ AF: 0.0192

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0225

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00209

GnomAD3 exomes AF: 0.00132 AC: 189 AN: 143696 Hom.: 8 AF XY: 0.00154 AC XY: 126 AN XY: 81758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000880

Gnomad ASJ exome AF: 0.00512

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00609

Gnomad FIN exome AF: 0.000312

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.00139

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00167 AC: 1616 AN: 969846 Hom.: 81 Cov.: 13 AF XY: 0.00214 AC XY: 1072 AN XY: 500328

Gnomad4 AFR exome AF: 0.0000928

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00939

Gnomad4 EAS exome AF: 0.0000843

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.000360

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00215 AC: 160 AN: 74254 Hom.: 1 Cov.: 31 AF XY: 0.00267 AC XY: 94 AN XY: 35170

Gnomad4 AFR AF: 0.000135

Gnomad4 AMR AF: 0.00312

Gnomad4 ASJ AF: 0.0192

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0294

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00206

Alfa AF: 0.000759 Hom.: 0

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

Invitae

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.6
Dann	Benign	0.80

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: rs773419952; hg19: chr5-96101044;