5-96727539-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001750.7(CAST):c.378+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,532,896 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (12 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.383

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-96727539-T-C is Benign according to our data. Variant chr5-96727539-T-C is described in ClinVar as [Benign]. Clinvar id is 720265.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.378+9T>C		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.378+9T>C		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152160 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00366 AC: 844 AN: 230394 Hom.: 5 AF XY: 0.00359 AC XY: 449 AN XY: 125068

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00850

Gnomad ASJ exome AF: 0.000209

Gnomad EAS exome AF: 0.0000599

Gnomad SAS exome AF: 0.00341

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.00189 AC: 2606 AN: 1380618 Hom.: 12 Cov.: 20 AF XY: 0.00201 AC XY: 1384 AN XY: 689702

Gnomad4 AFR exome AF: 0.000225

Gnomad4 AMR exome AF: 0.00719

Gnomad4 ASJ exome AF: 0.0000793

Gnomad4 EAS exome AF: 0.0000263

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152278 Hom.: 2 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74448

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00252 Hom.: 1

Bravo AF: 0.00136

Asia WGS AF: 0.00202 AC: 7 AN: 3470

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

Invitae

Dec 18, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.7
Dann	Benign	0.45

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: rs71630749; hg19: chr5-96063243;