5-96754272-A-G

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.1626+111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 736,358 control chromosomes in the GnomAD database, including 50,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11050 hom., cov: 33)
  • Exomes 𝑓: 0.36 (39590 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.761

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=-0.88).
• BP6: Variant 5-96754272-A-G is Benign according to our data. Variant chr5-96754272-A-G is described in ClinVar as [Benign]. Clinvar id is 1182630.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.1626+111A>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1626+111A>G		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56585 AN: 152078 Hom.: 11020 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.355 AC: 207607 AN: 584160 Hom.: 39590 AF XY: 0.353 AC XY: 110377 AN XY: 312358

Gnomad4 AFR exome AF: 0.439

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.579

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.371

Gnomad4 NFE exome AF: 0.318

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.372 AC: 56661 AN: 152198 Hom.: 11050 Cov.: 33 AF XY: 0.376 AC XY: 28012 AN XY: 74404

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.351

Alfa AF: 0.337 Hom.: 4929

Bravo AF: 0.381

Asia WGS AF: 0.454 AC: 1581 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	-0.88
Cadd	Benign	0.45
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs27772; hg19: chr5-96089976; COSMIC: COSV57786483; COSMIC: COSV57786483;