5-96757286-A-G

Variant names:

• chr5-96757286-A-G
• rs28081
• NM_001750.7:c.1711-158A>G

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.1711-158A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 152,194 control chromosomes in the GnomAD database, including 51,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.82 (51293 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.76
• Publications: 17 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=-0.98).
• BP6: Variant 5-96757286-A-G is Benign according to our data. Variant chr5-96757286-A-G is described in ClinVar as [Benign]. Clinvar id is 1258514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1711-158A>G		intron_variant	Intron 22 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1711-158A>G		intron_variant	Intron 22 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124457 AN: 152076 Hom.: 51235 Cov.: 33

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.814

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

GnomAD4 genome AF: 0.818 AC: 124569 AN: 152194 Hom.: 51293 Cov.: 33 AF XY: 0.819 AC XY: 60956 AN XY: 74414

African (AFR) AF: 0.761 AC: 31599 AN: 41498

American (AMR) AF: 0.876 AC: 13404 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2872 AN: 3472

East Asian (EAS) AF: 0.635 AC: 3292 AN: 5186

South Asian (SAS) AF: 0.813 AC: 3922 AN: 4822

European-Finnish (FIN) AF: 0.830 AC: 8801 AN: 10604

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.852 AC: 57939 AN: 67996

Other (OTH) AF: 0.815 AC: 1721 AN: 2112

Alfa AF: 0.840 Hom.: 229250

Bravo AF: 0.818

Asia WGS AF: 0.758 AC: 2639 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.053
DANN	Benign	0.36
PhyloP100		-1.8
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: rs28081; hg19: chr5-96092990;