5-96471275-T-C

Variant names:

• chr5-96471275-T-C
• rs269853
• NM_001423250.1:c.-175+91623T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001423250.1(CAST):​c.-175+91623T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 151,926 control chromosomes in the GnomAD database, including 19,920 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 0.50 (19920 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• 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, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001423250.1		c.-175+91623T>C		intron	N/A	NP_001410179.1	P20810-1
	CAST	NM_001423251.1		c.-175+91623T>C		intron	N/A	NP_001410180.1	P20810-2
	CAST	NM_001423252.1		c.-175+91623T>C		intron	N/A	NP_001410181.1	P20810-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000718093.1		c.-175+91623T>C		intron	N/A	ENSP00000520668.1	A0ABB0MV66
	CAST	ENST00000718091.1		c.-175+91623T>C		intron	N/A	ENSP00000520667.1	A0ABB0MV65
	CAST	ENST00000718090.1		n.240+91623T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75870 AN: 151806 Hom.: 19872 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.500 AC: 75987 AN: 151926 Hom.: 19920 Cov.: 32 AF XY: 0.496 AC XY: 36841 AN XY: 74264

African (AFR) AF: 0.663 AC: 27493 AN: 41454

American (AMR) AF: 0.488 AC: 7446 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1587 AN: 3460

East Asian (EAS) AF: 0.512 AC: 2650 AN: 5180

South Asian (SAS) AF: 0.360 AC: 1735 AN: 4824

European-Finnish (FIN) AF: 0.402 AC: 4245 AN: 10552

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28978 AN: 67886

Other (OTH) AF: 0.517 AC: 1091 AN: 2110

Alfa AF: 0.456 Hom.: 50662

Bravo AF: 0.519

Asia WGS AF: 0.495 AC: 1721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.57
PhyloP100		-1.0

Splicing

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

Other links and lift over

dbSNP: rs269853; hg19: chr5-95806979;