5-96695582-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.139-254A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 152,090 control chromosomes in the GnomAD database, including 9,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.33 (9464 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.67

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=-0.89).
• BP6: Variant 5-96695582-A-G is Benign according to our data. Variant chr5-96695582-A-G is described in ClinVar as [Benign]. Clinvar id is 1178477.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.139-254A>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.139-254A>G		intron_variant			NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49621 AN: 151972 Hom.: 9462 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.371

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

GnomAD4 genome AF: 0.326 AC: 49624 AN: 152090 Hom.: 9464 Cov.: 32 AF XY: 0.322 AC XY: 23975 AN XY: 74360

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.374

Alfa AF: 0.237 Hom.: 633

Bravo AF: 0.314

Asia WGS AF: 0.249 AC: 866 AN: 3474

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 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.037
Dann	Benign	0.43

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35015183; hg19: chr5-96031286;