rs4254932

Positions:

• chr5-96639483-A-C
• chr5-96639483-A-T

Variant summary

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

The ENST00000505143.5(CAST):​c.61-36056A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,196 control chromosomes in the GnomAD database, including 3,156 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 0.18 (3156 hom., cov: 32)
• Consequence: CAST ENST00000505143.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311

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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 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.61-36056A>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27320 AN: 152078 Hom.: 3156 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.180 AC: 27331 AN: 152196 Hom.: 3156 Cov.: 32 AF XY: 0.176 AC XY: 13076 AN XY: 74416

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.0844

Gnomad4 FIN AF: 0.0810

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.179

Alfa AF: 0.133 Hom.: 936

Bravo AF: 0.192

Asia WGS AF: 0.142 AC: 493 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
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: rs4254932; hg19: chr5-95975187;