rs261967

Variant names:

• chr5-96514546-A-C
• rs261967
• NM_001423250.1:c.-175+134894A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-96514546-A-C
• chr5-96514546-A-G
• chr5-96514546-A-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.-175+134894A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,954 control chromosomes in the GnomAD database, including 13,784 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 0.42 (13784 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 40 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-175+134894A>C		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-175+134894A>C		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-175+134894A>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.-175+134894A>C		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000718091.1	c.-175+134894A>C		intron_variant	Intron 3 of 11			ENSP00000520667.1
CAST	ENST00000718090.1	n.241-116421A>C		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64180 AN: 151836 Hom.: 13767 Cov.: 31

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.423 AC: 64253 AN: 151954 Hom.: 13784 Cov.: 31 AF XY: 0.431 AC XY: 32001 AN XY: 74254

African (AFR) AF: 0.393 AC: 16296 AN: 41440

American (AMR) AF: 0.455 AC: 6958 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3470

East Asian (EAS) AF: 0.440 AC: 2274 AN: 5174

South Asian (SAS) AF: 0.395 AC: 1900 AN: 4810

European-Finnish (FIN) AF: 0.567 AC: 5980 AN: 10538

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.416 AC: 28258 AN: 67926

Other (OTH) AF: 0.402 AC: 848 AN: 2112

Alfa AF: 0.419 Hom.: 32918

Bravo AF: 0.414

Asia WGS AF: 0.450 AC: 1561 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		0.071

Splicing

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

Other links and lift over

dbSNP: rs261967; hg19: chr5-95850250;