rs4077817

Variant names:

• chr5-96246669-C-T
• rs4077817
• NM_001423250.1:c.-333-71804C>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.-333-71804C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,122 control chromosomes in the GnomAD database, including 1,571 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 0.13 (1571 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351
• Publications: 1 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-333-71804C>T		intron_variant	Intron 3 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-654-71804C>T		intron_variant	Intron 2 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-333-71804C>T		intron_variant	Intron 2 of 33		NP_001410181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000502645.3	n.109-62055C>T		intron_variant	Intron 2 of 5	5
CAST	ENST00000511775.1	n.36-71804C>T		intron_variant	Intron 1 of 1	4
CAST	ENST00000718089.1	n.135-71804C>T		intron_variant	Intron 2 of 6
CAST	ENST00000718090.1	n.153+108592C>T		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19109 AN: 152002 Hom.: 1565 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0771

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.107

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

GnomAD4 genome AF: 0.126 AC: 19141 AN: 152122 Hom.: 1571 Cov.: 31 AF XY: 0.125 AC XY: 9301 AN XY: 74364

African (AFR) AF: 0.204 AC: 8451 AN: 41476

American (AMR) AF: 0.145 AC: 2221 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 229 AN: 3470

East Asian (EAS) AF: 0.219 AC: 1129 AN: 5150

South Asian (SAS) AF: 0.156 AC: 751 AN: 4818

European-Finnish (FIN) AF: 0.0771 AC: 817 AN: 10600

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0763 AC: 5192 AN: 68008

Other (OTH) AF: 0.106 AC: 223 AN: 2108

Alfa AF: 0.102 Hom.: 145

Bravo AF: 0.134

Asia WGS AF: 0.209 AC: 728 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.65
PhyloP100		-0.35

Splicing

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

Other links and lift over

dbSNP: rs4077817; hg19: chr5-95582373;