rs13179048

Variant names:

• chr5-96207022-C-A
• rs13179048
• NM_001423250.1:c.-334+96017C>A

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+96017C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 151,870 control chromosomes in the GnomAD database, including 5,042 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 0.24 (5042 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• Publications: 28 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-334+96017C>A		intron_variant	Intron 3 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-655+96017C>A		intron_variant	Intron 2 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-334+96017C>A		intron_variant	Intron 2 of 33		NP_001410181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000502645.3	n.108+96017C>A		intron_variant	Intron 2 of 5	5
CAST	ENST00000507997.1	n.160-7953C>A		intron_variant	Intron 2 of 2	2
CAST	ENST00000511775.1	n.36-111451C>A		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36071 AN: 151752 Hom.: 5050 Cov.: 32

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.237 AC: 36048 AN: 151870 Hom.: 5042 Cov.: 32 AF XY: 0.236 AC XY: 17532 AN XY: 74224

African (AFR) AF: 0.0837 AC: 3473 AN: 41480

American (AMR) AF: 0.213 AC: 3243 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 990 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1666 AN: 5152

South Asian (SAS) AF: 0.316 AC: 1521 AN: 4814

European-Finnish (FIN) AF: 0.316 AC: 3337 AN: 10548

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21066 AN: 67870

Other (OTH) AF: 0.239 AC: 504 AN: 2110

Alfa AF: 0.294 Hom.: 5578

Bravo AF: 0.225

Asia WGS AF: 0.288 AC: 1001 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.67
PhyloP100		-0.67

Splicing

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

Other links and lift over

dbSNP: rs13179048; hg19: chr5-95542726;