rs786204842

Variant names:

• chr5-96729723-A-T
• rs786204842
• NM_001750.7:c.547A>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001750.7(CAST):​c.547A>T​(p.Lys183*) 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 benign 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
• Publications: 1 publications found

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]

CAST Gene-Disease associations (from GenCC):

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 189335.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.547A>T	p.Lys183*	stop_gained splice_region	Exon 8 of 32	NP_001741.4
	CAST	NM_001042441.3		c.490A>T	p.Lys164*	stop_gained splice_region	Exon 7 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.481A>T	p.Lys161*	stop_gained splice_region	Exon 7 of 31	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.547A>T	p.Lys183*	stop_gained splice_region	Exon 8 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.298A>T	p.Lys100*	stop_gained splice_region	Exon 6 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.298A>T	p.Lys100*	stop_gained splice_region	Exon 8 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.81
Vest4		0.91
ClinPred		1.0	D
GERP RS		-0.34
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204842; hg19: chr5-96065427;