5-96722658-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001750.7(CAST):c.230C>G(p.Ala77Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAST NM_001750.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.786

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060520172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.230C>G	p.Ala77Gly	missense_variant	4/32	ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.230C>G	p.Ala77Gly	missense_variant	4/32		NM_001750.7	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460664 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

The c.230C>G (p.A77G) alteration is located in exon 4 (coding exon 4) of the CAST gene. This alteration results from a C to G substitution at nucleotide position 230, causing the alanine (A) at amino acid position 77 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	7.7
Dann	Benign	0.79
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.061	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.20	T;T;T;T;T;T;D;D;D;T
Sift4G	Benign	0.23	T;T;T;T;T;T;D;T;T;T
Polyphen		0.59	.;P;.;.;.;.;.;.;.;.
Vest4		0.17, 0.19, 0.23, 0.24
MutPred		0.18		.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;.;.;.;
MVP		0.17
MPC		0.070
ClinPred		0.32	T
GERP RS		0.74
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
gMVP		0.045

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-96058362;