rs10476552

Variant names:

• chr5-96373428-T-C
• rs10476552
• NM_001423250.1:c.-261-6138T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-96373428-T-C
• chr5-96373428-T-G

Variant summary

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

The NM_001423250.1(CAST):​c.-261-6138T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,194 control chromosomes in the GnomAD database, including 5,372 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 0.26 (5372 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.839
• Publications: 5 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=-0.67).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-261-6138T>C		intron_variant	Intron 4 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-261-6138T>C		intron_variant	Intron 4 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-261-6138T>C		intron_variant	Intron 3 of 33		NP_001410181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000718093.1	c.-261-6138T>C		intron_variant	Intron 2 of 30			ENSP00000520668.1
CAST	ENST00000718091.1	c.-261-6138T>C		intron_variant	Intron 2 of 11			ENSP00000520667.1
CAST	ENST00000502645.3	n.340-6138T>C		intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40059 AN: 152076 Hom.: 5373 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.263 AC: 40073 AN: 152194 Hom.: 5372 Cov.: 32 AF XY: 0.263 AC XY: 19566 AN XY: 74408

African (AFR) AF: 0.218 AC: 9065 AN: 41534

American (AMR) AF: 0.211 AC: 3235 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1049 AN: 3470

East Asian (EAS) AF: 0.317 AC: 1645 AN: 5184

South Asian (SAS) AF: 0.319 AC: 1536 AN: 4822

European-Finnish (FIN) AF: 0.305 AC: 3229 AN: 10584

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.287 AC: 19520 AN: 67986

Other (OTH) AF: 0.272 AC: 576 AN: 2116

Alfa AF: 0.281 Hom.: 19195

Bravo AF: 0.257

Asia WGS AF: 0.318 AC: 1104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.84

Splicing

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

Other links and lift over

dbSNP: rs10476552; hg19: chr5-95709132;