rs10515244

chr5-96742633-C-Gchr5-96742633-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.1099-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,505,340 control chromosomes in the GnomAD database, including 11,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.094 (883 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10656 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.374

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-96742633-C-G is Benign according to our data. Variant chr5-96742633-C-G is described in ClinVar as [Benign]. Clinvar id is 1221320.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.1099-22C>G		intron_variant		ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1099-22C>G		intron_variant			NM_001750.7	A2
	ENST00000502568.1	n.66G>C		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14319 AN: 152026 Hom.: 882 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.102 AC: 25358 AN: 248328 Hom.: 1587 AF XY: 0.105 AC XY: 14093 AN XY: 134230

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0697

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00132

Gnomad SAS exome AF: 0.0727

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.120 AC: 162912 AN: 1353194 Hom.: 10656 Cov.: 21 AF XY: 0.120 AC XY: 81475 AN XY: 679548

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0738

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.000741

Gnomad4 SAS exome AF: 0.0756

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.0941 AC: 14319 AN: 152146 Hom.: 883 Cov.: 32 AF XY: 0.0941 AC XY: 6999 AN XY: 74360

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0785

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.122

Alfa AF: 0.113 Hom.: 185

Bravo AF: 0.0888

Asia WGS AF: 0.0320 AC: 112 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	-0.66
Cadd	Benign	2.0
Dann	Benign	0.80

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: rs10515244; hg19: chr5-96078337; COSMIC: COSV57784020; COSMIC: COSV57784020;