rs4869272

Variant names:

• chr5-96203744-C-T
• rs4869272
• NM_001423250.1:c.-334+92739C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001423250.1(CAST):​c.-334+92739C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 151,878 control chromosomes in the GnomAD database, including 39,849 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39849 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 37 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

LOC101929710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001423250.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001423250.1		c.-334+92739C>T		intron	N/A	NP_001410179.1
	CAST	NM_001423251.1		c.-655+92739C>T		intron	N/A	NP_001410180.1
	CAST	NM_001423252.1		c.-334+92739C>T		intron	N/A	NP_001410181.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000502645.3	TSL:5	n.108+92739C>T		intron	N/A
	CAST	ENST00000507997.1	TSL:2	n.160-11231C>T		intron	N/A
	CAST	ENST00000511775.1	TSL:4	n.36-114729C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109610 AN: 151760 Hom.: 39792 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.809

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.730

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.723 AC: 109734 AN: 151878 Hom.: 39849 Cov.: 31 AF XY: 0.724 AC XY: 53704 AN XY: 74204

African (AFR) AF: 0.787 AC: 32616 AN: 41464

American (AMR) AF: 0.773 AC: 11743 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2430 AN: 3472

East Asian (EAS) AF: 0.676 AC: 3482 AN: 5152

South Asian (SAS) AF: 0.654 AC: 3150 AN: 4818

European-Finnish (FIN) AF: 0.682 AC: 7205 AN: 10566

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46617 AN: 67884

Other (OTH) AF: 0.732 AC: 1548 AN: 2116

Alfa AF: 0.696 Hom.: 165864

Bravo AF: 0.730

Asia WGS AF: 0.691 AC: 2400 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0030
DANN	Benign	0.43
PhyloP100		-1.7

Splicing

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

Other links and lift over

dbSNP: rs4869272; hg19: chr5-95539448;