rs786204842

Positions:

• chr5-96729723-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001750.7(CAST):​c.547A>T​(p.Lys183Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAST NM_001750.7 stop_gained, splice_region
• Scores: Splicing: ADA: 0.005842
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.805

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-96729723-A-T is Pathogenic according to our data. Variant chr5-96729723-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 189335.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAST	NM_001750.7	c.547A>T	p.Lys183Ter	stop_gained, splice_region_variant	8/32	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.547A>T	p.Lys183Ter	stop_gained, splice_region_variant	8/32		NM_001750.7	ENSP00000501872	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.60	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.91, 0.84, 0.87, 0.93, 0.91, 0.84, 0.84, 0.84, 0.90, 0.87
ClinPred		1.0	D
GERP RS		-0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0058
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.19		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: rs786204842; hg19: chr5-96065427;