5-96662496-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001750.7(CAST):c.74A>C(p.Glu25Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000074 in 1,406,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: CAST NM_001750.7 missense, splice_region
• Scores: Splicing: ADA: 0.9819
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.74A>C	p.Glu25Ala	missense_variant, splice_region_variant	1/32	ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.74A>C	p.Glu25Ala	missense_variant, splice_region_variant	1/32		NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151926 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000432 AC: 2 AN: 46304 Hom.: 0 AF XY: 0.0000725 AC XY: 2 AN XY: 27602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000789 AC: 99 AN: 1254396 Hom.: 0 Cov.: 34 AF XY: 0.0000844 AC XY: 52 AN XY: 615890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000327

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000825

Gnomad4 OTH exome AF: 0.0000582

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151926 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74200

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2022

This variant has not been reported in the literature in individuals affected with CAST-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 25 of the CAST protein (p.Glu25Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.39	N;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.052	T;T;T;D;T
Sift4G	Benign	0.16	T;D;D;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.23
MutPred		0.20		Loss of solvent accessibility (P = 0.0174);Loss of solvent accessibility (P = 0.0174);Loss of solvent accessibility (P = 0.0174);Loss of solvent accessibility (P = 0.0174);Loss of solvent accessibility (P = 0.0174);
MVP		0.62
MPC		0.25
ClinPred		0.18	T
GERP RS		2.3
gMVP		0.068

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs924323747; hg19: chr5-95998200;