5-96112290-C-T

Variant names:

• chr5-96112290-C-T
• rs6865159
• NM_001423250.1:c.-334+1285C>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.-334+1285C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 152,090 control chromosomes in the GnomAD database, including 46,228 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 0.78 (46228 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• Publications: 4 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.887 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001423250.1		c.-334+1285C>T		intron	N/A	NP_001410179.1
	CAST	NM_001423251.1		c.-655+1285C>T		intron	N/A	NP_001410180.1
	CAST	NM_001423252.1		c.-334+1285C>T		intron	N/A	NP_001410181.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000502645.3	TSL:5	n.108+1285C>T		intron	N/A
	CAST	ENST00000507997.1	TSL:2	n.159+1285C>T		intron	N/A
	CAST	ENST00000511775.1	TSL:4	n.35+150254C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117787 AN: 151972 Hom.: 46190 Cov.: 31

Gnomad AFR AF: 0.894

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.827

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.727

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

GnomAD4 genome AF: 0.775 AC: 117876 AN: 152090 Hom.: 46228 Cov.: 31 AF XY: 0.775 AC XY: 57629 AN XY: 74338

African (AFR) AF: 0.895 AC: 37163 AN: 41540

American (AMR) AF: 0.654 AC: 9972 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2293 AN: 3468

East Asian (EAS) AF: 0.738 AC: 3817 AN: 5170

South Asian (SAS) AF: 0.827 AC: 3992 AN: 4828

European-Finnish (FIN) AF: 0.827 AC: 8737 AN: 10562

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.727 AC: 49433 AN: 67968

Other (OTH) AF: 0.721 AC: 1523 AN: 2112

Alfa AF: 0.735 Hom.: 159469

Bravo AF: 0.767

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.53
PhyloP100		-0.43

Splicing

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

Other links and lift over

dbSNP: rs6865159; hg19: chr5-95447994;