rs26503

chr5-96742605-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):c.1099-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,107,250 control chromosomes in the GnomAD database, including 283,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35610 hom., cov: 31)
  • Exomes 𝑓: 0.72 (248292 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.155

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-96742605-G-A is Benign according to our data. Variant chr5-96742605-G-A is described in ClinVar as [Benign]. Clinvar id is 1241904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.1099-50G>A		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1099-50G>A		intron_variant			NM_001750.7	A2
	ENST00000502568.1	n.94C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103358 AN: 151852 Hom.: 35578 Cov.: 31

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.675

GnomAD3 exomes AF: 0.713 AC: 163908 AN: 229862 Hom.: 59115 AF XY: 0.709 AC XY: 88145 AN XY: 124376

Gnomad AFR exome AF: 0.567

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.623

Gnomad SAS exome AF: 0.638

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.716

GnomAD4 exome AF: 0.718 AC: 685775 AN: 955280 Hom.: 248292 Cov.: 12 AF XY: 0.716 AC XY: 354812 AN XY: 495824

Gnomad4 AFR exome AF: 0.556

Gnomad4 AMR exome AF: 0.837

Gnomad4 ASJ exome AF: 0.605

Gnomad4 EAS exome AF: 0.686

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.734

Gnomad4 NFE exome AF: 0.733

Gnomad4 OTH exome AF: 0.692

GnomAD4 genome AF: 0.681 AC: 103434 AN: 151970 Hom.: 35610 Cov.: 31 AF XY: 0.682 AC XY: 50608 AN XY: 74238

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.643

Gnomad4 SAS AF: 0.641

Gnomad4 FIN AF: 0.732

Gnomad4 NFE AF: 0.731

Gnomad4 OTH AF: 0.676

Alfa AF: 0.694 Hom.: 12115

Bravo AF: 0.680

Asia WGS AF: 0.663 AC: 2309 AN: 3478

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

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.4
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs26503; hg19: chr5-96078309; COSMIC: COSV57785672; COSMIC: COSV57785672;