rs151835

Variant names:

• chr5-96735278-A-G
• rs151835
• NM_001750.7:c.631-894A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-96735278-A-G
• chr5-96735278-A-T

Variant summary

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

The NM_001750.7(CAST):​c.631-894A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 152,172 control chromosomes in the GnomAD database, including 38,653 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 0.71 (38653 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.78
• Publications: 15 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.631-894A>G		intron_variant	Intron 9 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.631-894A>G		intron_variant	Intron 9 of 31		NM_001750.7	ENSP00000501872.1
CAST	ENST00000508117.6	n.*155-894A>G		intron_variant	Intron 7 of 7	5		ENSP00000422466.1

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108191 AN: 152054 Hom.: 38621 Cov.: 33

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.696

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

GnomAD4 genome AF: 0.712 AC: 108272 AN: 152172 Hom.: 38653 Cov.: 33 AF XY: 0.712 AC XY: 52936 AN XY: 74382

African (AFR) AF: 0.675 AC: 28034 AN: 41510

American (AMR) AF: 0.778 AC: 11904 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2081 AN: 3470

East Asian (EAS) AF: 0.653 AC: 3371 AN: 5162

South Asian (SAS) AF: 0.644 AC: 3110 AN: 4830

European-Finnish (FIN) AF: 0.732 AC: 7750 AN: 10586

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.732 AC: 49777 AN: 68004

Other (OTH) AF: 0.695 AC: 1468 AN: 2112

Alfa AF: 0.724 Hom.: 166415

Bravo AF: 0.716

Asia WGS AF: 0.676 AC: 2354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.084
DANN	Benign	0.35
PhyloP100		-3.8
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: rs151835; hg19: chr5-96070982;