rs4434401

chr5-96703321-T-C

Variant summary

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

The NM_001750.7(CAST):c.210+7414T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 151,826 control chromosomes in the GnomAD database, including 15,804 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 0.45 (15804 hom., cov: 30)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01

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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.210+7414T>C		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.210+7414T>C		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68446 AN: 151708 Hom.: 15778 Cov.: 30

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.484

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

GnomAD4 genome AF: 0.451 AC: 68511 AN: 151826 Hom.: 15804 Cov.: 30 AF XY: 0.445 AC XY: 33012 AN XY: 74182

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.401

Gnomad4 ASJ AF: 0.536

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.370

Gnomad4 FIN AF: 0.425

Gnomad4 NFE AF: 0.504

Gnomad4 OTH AF: 0.485

Alfa AF: 0.483 Hom.: 4760

Bravo AF: 0.452

Asia WGS AF: 0.297 AC: 1036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.6
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4434401; hg19: chr5-96039025; COSMIC: COSV57783769;