rs4254932

Variant names:

• chr5-96639483-A-C
• rs4254932
• NM_001423250.1:c.-174-36056A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-96639483-A-C
• chr5-96639483-A-T

Variant summary

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

The NM_001423250.1(CAST):​c.-174-36056A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,196 control chromosomes in the GnomAD database, including 3,156 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 0.18 (3156 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-174-36056A>C		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-174-36056A>C		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-174-36056A>C		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.-174-36056A>C		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000505143.6	c.-174-36056A>C		intron_variant	Intron 1 of 11	3		ENSP00000422957.2
CAST	ENST00000718091.1	c.-174-36056A>C		intron_variant	Intron 3 of 11			ENSP00000520667.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27320 AN: 152078 Hom.: 3156 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.180 AC: 27331 AN: 152196 Hom.: 3156 Cov.: 32 AF XY: 0.176 AC XY: 13076 AN XY: 74416

African (AFR) AF: 0.332 AC: 13783 AN: 41498

American (AMR) AF: 0.117 AC: 1784 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 546 AN: 3470

East Asian (EAS) AF: 0.168 AC: 870 AN: 5180

South Asian (SAS) AF: 0.0844 AC: 407 AN: 4824

European-Finnish (FIN) AF: 0.0810 AC: 859 AN: 10608

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8543 AN: 68016

Other (OTH) AF: 0.179 AC: 379 AN: 2116

Alfa AF: 0.133 Hom.: 1006

Bravo AF: 0.192

Asia WGS AF: 0.142 AC: 493 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	0.61
DANN	Benign	0.75
PhyloP100		-0.31

Splicing

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

Other links and lift over

dbSNP: rs4254932; hg19: chr5-95975187;