5-96728929-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):c.379-224A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 483,976 control chromosomes in the GnomAD database, including 12,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3085 hom., cov: 32)
  • Exomes 𝑓: 0.23 (9195 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-96728929-A-C is Benign according to our data. Variant chr5-96728929-A-C is described in ClinVar as [Benign]. Clinvar id is 1296751.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.379-224A>C		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.379-224A>C		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28834 AN: 152002 Hom.: 3083 Cov.: 32

Gnomad AFR AF: 0.0943

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.227 AC: 75315 AN: 331856 Hom.: 9195 Cov.: 0 AF XY: 0.227 AC XY: 39090 AN XY: 172528

Gnomad4 AFR exome AF: 0.0944

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.344

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.190 AC: 28832 AN: 152120 Hom.: 3085 Cov.: 32 AF XY: 0.195 AC XY: 14522 AN XY: 74356

Gnomad4 AFR AF: 0.0941

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.346

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.175

Alfa AF: 0.109 Hom.: 202

Bravo AF: 0.181

Asia WGS AF: 0.294 AC: 1025 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.5
Dann	Benign	0.73

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: rs27531; hg19: chr5-96064633;