5-96693264-G-A

Position:

• chr5-96693264-G-A

Variant summary

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

The NM_001750.7(CAST):​c.139-2572G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,096 control chromosomes in the GnomAD database, including 2,724 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 0.19 (2724 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175

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 (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.139-2572G>A		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.139-2572G>A		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28302 AN: 151978 Hom.: 2722 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.186 AC: 28308 AN: 152096 Hom.: 2724 Cov.: 33 AF XY: 0.190 AC XY: 14134 AN XY: 74344

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.173

Alfa AF: 0.199 Hom.: 386

Bravo AF: 0.178

Asia WGS AF: 0.257 AC: 896 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	2.2
DANN	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4869307; hg19: chr5-96028968;