rs10515242

Positions:

• chr5-96646971-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000505143.5(CAST):​c.61-28568A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 152,306 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.047 (254 hom., cov: 32)
• Consequence: CAST ENST00000505143.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000505143.5	c.61-28568A>C		intron_variant		3		ENSP00000422957

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7196 AN: 152188 Hom.: 256 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0726

Gnomad OTH AF: 0.0612

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0472 AC: 7195 AN: 152306 Hom.: 254 Cov.: 32 AF XY: 0.0444 AC XY: 3310 AN XY: 74480

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.0726

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0627 Hom.: 153

Bravo AF: 0.0492

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.61
DANN	Benign	0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10515242; hg19: chr5-95982675;