rs4434401

Variant names:

• chr5-96703321-T-C
• rs4434401
• NM_001750.7:c.210+7414T>C

Variant summary

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

The NM_001750.7(CAST):​c.210+7414T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 151,826 control chromosomes in the GnomAD database, including 15,804 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 0.45 (15804 hom., cov: 30)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 10 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. 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_001750.7	MANE Select	c.210+7414T>C		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.210+7414T>C		intron	N/A	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.210+7414T>C		intron	N/A	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.210+7414T>C		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.-40+7414T>C		intron	N/A	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.-40+7414T>C		intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68446 AN: 151708 Hom.: 15778 Cov.: 30

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.484

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

GnomAD4 genome AF: 0.451 AC: 68511 AN: 151826 Hom.: 15804 Cov.: 30 AF XY: 0.445 AC XY: 33012 AN XY: 74182

African (AFR) AF: 0.417 AC: 17257 AN: 41380

American (AMR) AF: 0.401 AC: 6115 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1860 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1126 AN: 5162

South Asian (SAS) AF: 0.370 AC: 1781 AN: 4812

European-Finnish (FIN) AF: 0.425 AC: 4470 AN: 10530

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34231 AN: 67902

Other (OTH) AF: 0.485 AC: 1024 AN: 2110

Alfa AF: 0.474 Hom.: 9969

Bravo AF: 0.452

Asia WGS AF: 0.297 AC: 1036 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.78
PhyloP100		-1.0
PromoterAI		-0.034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4434401; hg19: chr5-96039025; COSMIC: COSV57783769;