rs261212

Variant names:

• chr5-96605661-C-T
• rs261212
• NM_001423250.1:c.-174-69878C>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.-174-69878C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,884 control chromosomes in the GnomAD database, including 22,446 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 0.54 (22446 hom., cov: 33)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-174-69878C>T		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-174-69878C>T		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-174-69878C>T		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.-174-69878C>T		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000505143.6	c.-174-69878C>T		intron_variant	Intron 1 of 11	3		ENSP00000422957.2
CAST	ENST00000718091.1	c.-174-69878C>T		intron_variant	Intron 3 of 11			ENSP00000520667.1

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82459 AN: 151766 Hom.: 22409 Cov.: 33

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.510

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

GnomAD4 genome AF: 0.544 AC: 82552 AN: 151884 Hom.: 22446 Cov.: 33 AF XY: 0.544 AC XY: 40436 AN XY: 74276

African (AFR) AF: 0.594 AC: 24650 AN: 41472

American (AMR) AF: 0.545 AC: 8316 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1686 AN: 3460

East Asian (EAS) AF: 0.420 AC: 2171 AN: 5172

South Asian (SAS) AF: 0.436 AC: 2100 AN: 4818

European-Finnish (FIN) AF: 0.601 AC: 6326 AN: 10528

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35610 AN: 67862

Other (OTH) AF: 0.513 AC: 1081 AN: 2108

Alfa AF: 0.528 Hom.: 80321

Bravo AF: 0.541

Asia WGS AF: 0.478 AC: 1662 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		0.038

Splicing

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

Other links and lift over

dbSNP: rs261212; hg19: chr5-95941365;