rs1862609

Variant names:

• chr5-96750986-G-A
• rs1862609
• NM_001750.7:c.1524+304G>A

Variant summary

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

The NM_001750.7(CAST):​c.1524+304G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 151,796 control chromosomes in the GnomAD database, including 4,972 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 0.24 (4972 hom., cov: 31)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.655
• Publications: 22 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1524+304G>A		intron_variant	Intron 20 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1524+304G>A		intron_variant	Intron 20 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36848 AN: 151678 Hom.: 4969 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.228

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

GnomAD4 genome AF: 0.243 AC: 36865 AN: 151796 Hom.: 4972 Cov.: 31 AF XY: 0.239 AC XY: 17756 AN XY: 74176

African (AFR) AF: 0.134 AC: 5544 AN: 41362

American (AMR) AF: 0.217 AC: 3306 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3468

East Asian (EAS) AF: 0.0817 AC: 422 AN: 5166

South Asian (SAS) AF: 0.212 AC: 1018 AN: 4796

European-Finnish (FIN) AF: 0.298 AC: 3136 AN: 10528

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21782 AN: 67922

Other (OTH) AF: 0.227 AC: 479 AN: 2108

Alfa AF: 0.289 Hom.: 3800

Bravo AF: 0.231

Asia WGS AF: 0.165 AC: 573 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.40
PhyloP100		0.66
PromoterAI		0.0015	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: rs1862609; hg19: chr5-96086690;