rs4869305

chr5-96656663-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000505143.5(CAST):c.61-18876G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 152,184 control chromosomes in the GnomAD database, including 129 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 0.033 (129 hom., cov: 32)
• Consequence: CAST ENST00000505143.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792

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=-0.92).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0328 (4995/152184) while in subpopulation SAS AF= 0.0551 (266/4826). AF 95% confidence interval is 0.0497. There are 129 homozygotes in gnomad4. There are 2406 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 126 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000505143.5	c.61-18876G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4979 AN: 152066 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0383

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

GnomAD4 genome AF: 0.0328 AC: 4995 AN: 152184 Hom.: 129 Cov.: 32 AF XY: 0.0323 AC XY: 2406 AN XY: 74396

Gnomad4 AFR AF: 0.0447

Gnomad4 AMR AF: 0.0452

Gnomad4 ASJ AF: 0.0498

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.0551

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0249

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0297 Hom.: 35

Bravo AF: 0.0372

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.0
Dann	Benign	0.21

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4869305; hg19: chr5-95992367;