rs469532

Positions:

• chr5-96716286-T-G

Variant summary

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

The NM_001750.7(CAST):​c.211-6353T>G 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 152,154 control chromosomes in the GnomAD database, including 2,748 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 (2748 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700

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]

LOC107986363 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.211-6353T>G		intron_variant		ENST00000675179.1	NP_001741.4
LOC107986363	XR_001742454.2	n.8775T>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.211-6353T>G		intron_variant			NM_001750.7	ENSP00000501872	A2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28283 AN: 152036 Hom.: 2746 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.172

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

GnomAD4 genome AF: 0.186 AC: 28286 AN: 152154 Hom.: 2748 Cov.: 32 AF XY: 0.190 AC XY: 14137 AN XY: 74388

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.171

Alfa AF: 0.201 Hom.: 1454

Bravo AF: 0.178

Asia WGS AF: 0.260 AC: 906 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.34

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: rs469532; hg19: chr5-96051990;