rs4869307

Variant names:

• chr5-96693264-G-A
• rs4869307
• NM_001750.7:c.139-2572G>A

Variant summary

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

The NM_001750.7(CAST):​c.139-2572G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,096 control chromosomes in the GnomAD database, including 2,724 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 0.19 (2724 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• Publications: 3 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

CAST (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.139-2572G>A		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.139-2572G>A		intron	N/A	NP_001035906.1
	CAST	NM_001042442.3		c.139-2572G>A		intron	N/A	NP_001035907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.139-2572G>A		intron	N/A	ENSP00000501872.1
	CAST	ENST00000338252.7	TSL:1	c.-111-2572G>A		intron	N/A	ENSP00000343421.3
	CAST	ENST00000508830.5	TSL:5	c.139-2572G>A		intron	N/A	ENSP00000425721.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28302 AN: 151978 Hom.: 2722 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.186 AC: 28308 AN: 152096 Hom.: 2724 Cov.: 33 AF XY: 0.190 AC XY: 14134 AN XY: 74344

African (AFR) AF: 0.131 AC: 5457 AN: 41506

American (AMR) AF: 0.209 AC: 3201 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1162 AN: 5176

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4818

European-Finnish (FIN) AF: 0.258 AC: 2721 AN: 10548

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13725 AN: 67980

Other (OTH) AF: 0.173 AC: 365 AN: 2110

Alfa AF: 0.197 Hom.: 390

Bravo AF: 0.178

Asia WGS AF: 0.257 AC: 896 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.79
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4869307; hg19: chr5-96028968;