5-96727253-T-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.337-236T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,192 control chromosomes in the GnomAD database, including 5,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (5389 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0330

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 5-96727253-T-C is Benign according to our data. Variant chr5-96727253-T-C is described in ClinVar as [Benign]. Clinvar id is 1260567.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.337-236T>C		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.337-236T>C		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 39001 AN: 152074 Hom.: 5384 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.256 AC: 39029 AN: 152192 Hom.: 5389 Cov.: 33 AF XY: 0.251 AC XY: 18690 AN XY: 74410

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.0747

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.262

Alfa AF: 0.270 Hom.: 1295

Bravo AF: 0.250

Asia WGS AF: 0.176 AC: 609 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	1.7
Dann	Benign	0.79

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: rs11135479; hg19: chr5-96062957;