rs1421911

Variant names:

• chr5-96665243-A-G
• rs1421911
• NM_001750.7:c.75+2746A>G

Variant summary

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

The NM_001750.7(CAST):​c.75+2746A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,174 control chromosomes in the GnomAD database, including 4,405 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 0.21 (4405 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136
• Publications: 18 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.75+2746A>G		intron_variant	Intron 1 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.75+2746A>G		intron_variant	Intron 1 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31825 AN: 152056 Hom.: 4397 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.187

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

GnomAD4 genome AF: 0.209 AC: 31853 AN: 152174 Hom.: 4405 Cov.: 32 AF XY: 0.209 AC XY: 15573 AN XY: 74402

African (AFR) AF: 0.375 AC: 15540 AN: 41484

American (AMR) AF: 0.132 AC: 2025 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1704 AN: 5166

South Asian (SAS) AF: 0.241 AC: 1164 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1385 AN: 10602

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8796 AN: 68016

Other (OTH) AF: 0.190 AC: 401 AN: 2110

Alfa AF: 0.145 Hom.: 3323

Bravo AF: 0.215

Asia WGS AF: 0.266 AC: 924 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	5.2
DANN	Benign	0.61
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1421911; hg19: chr5-96000947;