5-96626713-A-G

Variant names:

• chr5-96626713-A-G
• rs261235
• NM_001423250.1:c.-174-48826A>G

Variant summary

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

The NM_001423250.1(CAST):​c.-174-48826A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 152,164 control chromosomes in the GnomAD database, including 60,708 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 0.89 (60708 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-174-48826A>G		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-174-48826A>G		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-174-48826A>G		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.-174-48826A>G		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000505143.6	c.-174-48826A>G		intron_variant	Intron 1 of 11	3		ENSP00000422957.2
CAST	ENST00000718091.1	c.-174-48826A>G		intron_variant	Intron 3 of 11			ENSP00000520667.1

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135707 AN: 152046 Hom.: 60640 Cov.: 31

Gnomad AFR AF: 0.935

Gnomad AMI AF: 0.809

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.952

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.872

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

GnomAD4 genome AF: 0.893 AC: 135833 AN: 152164 Hom.: 60708 Cov.: 31 AF XY: 0.896 AC XY: 66626 AN XY: 74380

African (AFR) AF: 0.935 AC: 38799 AN: 41512

American (AMR) AF: 0.894 AC: 13662 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3021 AN: 3472

East Asian (EAS) AF: 0.952 AC: 4929 AN: 5178

South Asian (SAS) AF: 0.877 AC: 4228 AN: 4820

European-Finnish (FIN) AF: 0.897 AC: 9487 AN: 10578

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58868 AN: 68004

Other (OTH) AF: 0.874 AC: 1848 AN: 2114

Alfa AF: 0.875 Hom.: 73694

Bravo AF: 0.894

Asia WGS AF: 0.929 AC: 3230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs261235; hg19: chr5-95962417;