rs754615

Positions:

• chr5-96750630-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001750.7(CAST):​c.1472G>C​(p.Cys491Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,610,838 control chromosomes in the GnomAD database, including 115,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9438 hom., cov: 31)
  • Exomes 𝑓: 0.37 (105620 hom.)
• Consequence: CAST NM_001750.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022271872).
• BP6: Variant 5-96750630-G-C is Benign according to our data. Variant chr5-96750630-G-C is described in ClinVar as [Benign]. Clinvar id is 1192697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.1472G>C	p.Cys491Ser	missense_variant	20/32	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1472G>C	p.Cys491Ser	missense_variant	20/32		NM_001750.7	ENSP00000501872	A2

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52791 AN: 151710 Hom.: 9430 Cov.: 31

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.335

GnomAD3 exomes AF: 0.329 AC: 82412 AN: 250846 Hom.: 14783 AF XY: 0.337 AC XY: 45735 AN XY: 135568

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.375 AC: 546799 AN: 1459010 Hom.: 105620 Cov.: 32 AF XY: 0.376 AC XY: 272665 AN XY: 725814

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.394

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.348 AC: 52825 AN: 151828 Hom.: 9438 Cov.: 31 AF XY: 0.344 AC XY: 25551 AN XY: 74202

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.336

Alfa AF: 0.379 Hom.: 8412

Bravo AF: 0.341

TwinsUK AF: 0.399 AC: 1479

ALSPAC AF: 0.394 AC: 1520

ESP6500AA AF: 0.322 AC: 1420

ESP6500EA AF: 0.381 AC: 3278

ExAC AF: 0.334 AC: 40484

Asia WGS AF: 0.258 AC: 896 AN: 3478

EpiCase AF: 0.398

EpiControl AF: 0.401

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.3
DANN	Benign	0.36
DEOGEN2	Benign	0.041	.;.;.;.;.;T;T;T;.;.;T;T;T;.;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.33	T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	.;.;.;.;.;N;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.8	N;N;N;N;N;N;.;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.65	T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.89	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;B;B;B;.;.;B;.;B;.;B;.
Vest4		0.022
MutPred		0.31		.;.;.;Gain of sheet (P = 0.0043);.;.;.;.;.;.;.;.;.;.;.;.;
MPC		0.035
ClinPred		0.0069	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.057
gMVP		0.048

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: rs754615; hg19: chr5-96086334; COSMIC: COSV57783373; COSMIC: COSV57783373;