NM_001750.7:c.1834-1789G>T

Variant names:

• chr5-96760485-G-T
• rs7356594
• NM_001750.7:c.1834-1789G>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.1834-1789G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 151,708 control chromosomes in the GnomAD database, including 4,915 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 0.24 (4915 hom., cov: 33)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.982
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1834-1789G>T		intron_variant	Intron 24 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1834-1789G>T		intron_variant	Intron 24 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36639 AN: 151590 Hom.: 4911 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.227

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.242 AC: 36657 AN: 151708 Hom.: 4915 Cov.: 33 AF XY: 0.238 AC XY: 17670 AN XY: 74128

African (AFR) AF: 0.134 AC: 5565 AN: 41452

American (AMR) AF: 0.214 AC: 3268 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 920 AN: 3456

East Asian (EAS) AF: 0.0795 AC: 412 AN: 5182

South Asian (SAS) AF: 0.214 AC: 1032 AN: 4818

European-Finnish (FIN) AF: 0.297 AC: 3128 AN: 10520

Middle Eastern (MID) AF: 0.241 AC: 69 AN: 286

European-Non Finnish (NFE) AF: 0.319 AC: 21597 AN: 67728

Other (OTH) AF: 0.226 AC: 476 AN: 2108

Alfa AF: 0.267 Hom.: 939

Bravo AF: 0.229

Asia WGS AF: 0.162 AC: 558 AN: 3446

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.3
DANN	Benign	0.81
PhyloP100		-0.98
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: rs7356594; hg19: chr5-96096189;