rs4869305

Variant names:

• chr5-96656663-G-A
• rs4869305
• NM_001423250.1:c.-174-18876G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001423250.1(CAST):​c.-174-18876G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 152,184 control chromosomes in the GnomAD database, including 129 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 0.033 (129 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 3 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=-0.92).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0328 (4995/152184) while in subpopulation SAS AF = 0.0551 (266/4826). AF 95% confidence interval is 0.0497. There are 129 homozygotes in GnomAd4. There are 2406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 129 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-174-18876G>A		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-174-18876G>A		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-174-18876G>A		intron_variant	Intron 4 of 33		NP_001410181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000718093.1	c.-174-18876G>A		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000505143.6	c.-174-18876G>A		intron_variant	Intron 1 of 11	3		ENSP00000422957.2
CAST	ENST00000718091.1	c.-174-18876G>A		intron_variant	Intron 3 of 11			ENSP00000520667.1

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4979 AN: 152066 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0383

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

GnomAD4 genome AF: 0.0328 AC: 4995 AN: 152184 Hom.: 129 Cov.: 32 AF XY: 0.0323 AC XY: 2406 AN XY: 74396

African (AFR) AF: 0.0447 AC: 1856 AN: 41502

American (AMR) AF: 0.0452 AC: 691 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5186

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4826

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10592

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0249 AC: 1696 AN: 68004

Other (OTH) AF: 0.0379 AC: 80 AN: 2110

Alfa AF: 0.0300 Hom.: 50

Bravo AF: 0.0372

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.21
PhyloP100		-0.79

Splicing

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

Other links and lift over

dbSNP: rs4869305; hg19: chr5-95992367;