rs261234

Variant names:

• chr5-96626749-T-C
• rs261234
• NM_001423250.1:c.-174-48790T>C

Variant summary

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

The NM_001423250.1(CAST):​c.-174-48790T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 152,048 control chromosomes in the GnomAD database, including 7,994 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 0.32 (7994 hom., cov: 32)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.649
• 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

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-174-48790T>C		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-174-48790T>C		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-174-48790T>C		intron_variant	Intron 4 of 33		NP_001410181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000718093.1	c.-174-48790T>C		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000505143.6	c.-174-48790T>C		intron_variant	Intron 1 of 11	3		ENSP00000422957.2
CAST	ENST00000718091.1	c.-174-48790T>C		intron_variant	Intron 3 of 11			ENSP00000520667.1

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48520 AN: 151930 Hom.: 7982 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.303

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

GnomAD4 genome AF: 0.319 AC: 48576 AN: 152048 Hom.: 7994 Cov.: 32 AF XY: 0.324 AC XY: 24106 AN XY: 74306

African (AFR) AF: 0.241 AC: 10012 AN: 41464

American (AMR) AF: 0.370 AC: 5654 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1449 AN: 3472

East Asian (EAS) AF: 0.339 AC: 1751 AN: 5172

South Asian (SAS) AF: 0.401 AC: 1932 AN: 4818

European-Finnish (FIN) AF: 0.383 AC: 4038 AN: 10552

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.334 AC: 22727 AN: 67978

Other (OTH) AF: 0.307 AC: 648 AN: 2112

Alfa AF: 0.335 Hom.: 7243

Bravo AF: 0.313

Asia WGS AF: 0.403 AC: 1404 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.4
DANN	Benign	0.42
PhyloP100		-0.65

Splicing

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

Other links and lift over

dbSNP: rs261234; hg19: chr5-95962453;