rs4400148

Positions:

• chr5-96653083-T-C

Variant summary

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

The ENST00000505143.5(CAST):​c.61-22456T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 152,098 control chromosomes in the GnomAD database, including 33,626 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 0.65 (33626 hom., cov: 32)
• Consequence: CAST ENST00000505143.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

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.61-22456T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98587 AN: 151980 Hom.: 33576 Cov.: 32

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.611

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

GnomAD4 genome AF: 0.649 AC: 98692 AN: 152098 Hom.: 33626 Cov.: 32 AF XY: 0.653 AC XY: 48538 AN XY: 74348

Gnomad4 AFR AF: 0.852

Gnomad4 AMR AF: 0.690

Gnomad4 ASJ AF: 0.474

Gnomad4 EAS AF: 0.799

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.530

Gnomad4 OTH AF: 0.609

Alfa AF: 0.551 Hom.: 47731

Bravo AF: 0.664

Asia WGS AF: 0.724 AC: 2517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.30
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4400148; hg19: chr5-95988787;