5-96746697-C-T

Variant names:

• chr5-96746697-C-T
• rs27851
• NM_001750.7:c.1284+272C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):​c.1284+272C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 152,290 control chromosomes in the GnomAD database, including 64,393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.92 (64393 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.450
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-96746697-C-T is Benign according to our data. Variant chr5-96746697-C-T is described in ClinVar as Benign. ClinVar VariationId is 1249890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.1284+272C>T		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.1227+272C>T		intron	N/A	NP_001035906.1
	CAST	NM_001042442.3		c.1218+272C>T		intron	N/A	NP_001035907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.1284+272C>T		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1035+272C>T		intron	N/A	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.996+272C>T		intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.919 AC: 139805 AN: 152172 Hom.: 64354 Cov.: 33

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.971

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.901

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.940

Gnomad OTH AF: 0.931

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

GnomAD4 genome AF: 0.919 AC: 139897 AN: 152290 Hom.: 64393 Cov.: 33 AF XY: 0.921 AC XY: 68554 AN XY: 74466

African (AFR) AF: 0.855 AC: 35524 AN: 41526

American (AMR) AF: 0.949 AC: 14524 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3076 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5184 AN: 5192

South Asian (SAS) AF: 0.902 AC: 4354 AN: 4828

European-Finnish (FIN) AF: 0.956 AC: 10153 AN: 10616

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.940 AC: 63955 AN: 68032

Other (OTH) AF: 0.932 AC: 1970 AN: 2114

Alfa AF: 0.926 Hom.: 34529

Bravo AF: 0.915

Asia WGS AF: 0.957 AC: 3327 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.0
DANN	Benign	0.62
PhyloP100		0.45
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: rs27851; hg19: chr5-96082401;