rs1021505

Variant names:

• chr5-96015733-T-A
• rs1021505
• NM_001423250.1:c.-406+41251T>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.-406+41251T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,950 control chromosomes in the GnomAD database, including 25,255 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 0.57 (25255 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.377
• Publications: 1 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-406+41251T>A		intron_variant	Intron 2 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-727+53697T>A		intron_variant	Intron 1 of 34		NP_001410180.1
CAST	NM_001423253.1	c.-262+54147T>A		intron_variant	Intron 1 of 31		NP_001410182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000502645.3	n.36+53697T>A		intron_variant	Intron 1 of 5	5
CAST	ENST00000511775.1	n.35+53697T>A		intron_variant	Intron 1 of 1	4
CAST	ENST00000718075.1	n.33+53697T>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86621 AN: 151832 Hom.: 25250 Cov.: 31

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.572

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

GnomAD4 genome AF: 0.570 AC: 86650 AN: 151950 Hom.: 25255 Cov.: 31 AF XY: 0.569 AC XY: 42239 AN XY: 74276

African (AFR) AF: 0.476 AC: 19706 AN: 41406

American (AMR) AF: 0.488 AC: 7447 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1876 AN: 3468

East Asian (EAS) AF: 0.449 AC: 2313 AN: 5154

South Asian (SAS) AF: 0.580 AC: 2801 AN: 4826

European-Finnish (FIN) AF: 0.676 AC: 7138 AN: 10560

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43427 AN: 67966

Other (OTH) AF: 0.566 AC: 1194 AN: 2108

Alfa AF: 0.608 Hom.: 3531

Bravo AF: 0.553

Asia WGS AF: 0.468 AC: 1630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.9
DANN	Benign	0.75
PhyloP100		0.38

Splicing

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

Other links and lift over

dbSNP: rs1021505; hg19: chr5-95351437;