5-96726913-C-T

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.336+54C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,226,468 control chromosomes in the GnomAD database, including 8,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (783 hom., cov: 32)
  • Exomes 𝑓: 0.11 (7317 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308

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 5-96726913-C-T is Benign according to our data. Variant chr5-96726913-C-T is described in ClinVar as [Benign]. Clinvar id is 1287556.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.336+54C>T		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.336+54C>T		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.0892 AC: 13572 AN: 152130 Hom.: 783 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0933

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0773

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.108 AC: 116394 AN: 1074220 Hom.: 7317 AF XY: 0.109 AC XY: 60047 AN XY: 551806

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.0680

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.000848

Gnomad4 SAS exome AF: 0.0740

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0891 AC: 13569 AN: 152248 Hom.: 783 Cov.: 32 AF XY: 0.0888 AC XY: 6608 AN XY: 74436

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.0932

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0778

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.111

Alfa AF: 0.106 Hom.: 113

Bravo AF: 0.0839

Asia WGS AF: 0.0320 AC: 113 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

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.4
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17478897; hg19: chr5-96062617; COSMIC: COSV57785837; COSMIC: COSV57785837;