CAST p.Ser306Ser

Variant names:

• chr5-96740780-T-T
• ENST00000675179.1:c.

Your query was ambiguous. Multiple possible variants found:

• chr5-96740781--
• chr5-96740783-G-T
• chr5-96740783-G-C
• chr5-96740783-G-A
• chr5-96740781-TCG-AGT
• chr5-96740781-TCG-AGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000675179.1(CAST):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAST ENST00000675179.1 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

CAST (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675179.1. 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_001423250.1		c.		intron	N/A	NP_001410179.1	P20810-1
	CAST	NM_001423251.1		c.		intron	N/A	NP_001410180.1	P20810-2
	CAST	NM_001423252.1		c.		intron	N/A	NP_001410181.1	P20810-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.		exon_region	Exon 13 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.		exon_region	Exon 11 of 30	ENSP00000339914.3
	CAST	ENST00000309190.9	TSL:1	c.		exon_region	Exon 10 of 29	ENSP00000312523.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-96076484;