NM_001423250.1:c.-405-17954G>A

Variant names:

• chr5-96092980-G-A
• rs7734985
• NM_001423250.1:c.-405-17954G>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.-405-17954G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 151,960 control chromosomes in the GnomAD database, including 30,862 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 0.64 (30862 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 7 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=-0.54).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.657 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.-405-17954G>A		intron	N/A	NP_001410179.1
	CAST	NM_001423251.1		c.-726-17954G>A		intron	N/A	NP_001410180.1
	CAST	NM_001423252.1		c.-405-17954G>A		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.37-17954G>A		intron	N/A
	CAST	ENST00000507997.1	TSL:2	n.88-17954G>A		intron	N/A
	CAST	ENST00000511775.1	TSL:4	n.35+130944G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96466 AN: 151842 Hom.: 30842 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.607

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

GnomAD4 genome AF: 0.635 AC: 96528 AN: 151960 Hom.: 30862 Cov.: 32 AF XY: 0.635 AC XY: 47167 AN XY: 74282

African (AFR) AF: 0.664 AC: 27493 AN: 41430

American (AMR) AF: 0.503 AC: 7684 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1958 AN: 3468

East Asian (EAS) AF: 0.503 AC: 2596 AN: 5160

South Asian (SAS) AF: 0.677 AC: 3254 AN: 4810

European-Finnish (FIN) AF: 0.721 AC: 7614 AN: 10554

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43846 AN: 67964

Other (OTH) AF: 0.602 AC: 1266 AN: 2104

Alfa AF: 0.637 Hom.: 9678

Bravo AF: 0.620

Asia WGS AF: 0.551 AC: 1915 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		0.15

Splicing

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

Other links and lift over

dbSNP: rs7734985; hg19: chr5-95428684;