NM_001423250.1:c.-514+3723G>A

Variant names:

• chr5-95965759-G-A
• rs918629
• NM_001423250.1:c.-514+3723G>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.-514+3723G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,050 control chromosomes in the GnomAD database, including 13,970 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 0.39 (13970 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.159
• Publications: 6 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

ENSG00000250955 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 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.-514+3723G>A		intron	N/A	NP_001410179.1
	CAST	NM_001423251.1		c.-727+3723G>A		intron	N/A	NP_001410180.1
	CAST	NM_001423253.1		c.-262+4173G>A		intron	N/A	NP_001410182.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000502645.3	TSL:5	n.36+3723G>A		intron	N/A
	ENSG00000250955	ENST00000506070.1	TSL:3	n.319-508C>T		intron	N/A
	CAST	ENST00000511775.1	TSL:4	n.35+3723G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59602 AN: 151932 Hom.: 13932 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.393 AC: 59688 AN: 152050 Hom.: 13970 Cov.: 32 AF XY: 0.400 AC XY: 29736 AN XY: 74332

African (AFR) AF: 0.606 AC: 25117 AN: 41468

American (AMR) AF: 0.377 AC: 5765 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3466

East Asian (EAS) AF: 0.836 AC: 4335 AN: 5188

South Asian (SAS) AF: 0.458 AC: 2210 AN: 4826

European-Finnish (FIN) AF: 0.346 AC: 3650 AN: 10540

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16849 AN: 67958

Other (OTH) AF: 0.351 AC: 740 AN: 2110

Alfa AF: 0.293 Hom.: 24002

Bravo AF: 0.407

Asia WGS AF: 0.642 AC: 2228 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.60
PhyloP100		0.16

Splicing

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

Other links and lift over

dbSNP: rs918629; hg19: chr5-95301463;