chr5-96758990-T-G

Variant names:

• chr5-96758990-T-G
• rs27037
• NM_001750.7:c.1833+1336T>G

Variant summary

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

The NM_001750.7(CAST):​c.1833+1336T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 151,948 control chromosomes in the GnomAD database, including 39,172 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 0.72 (39172 hom., cov: 31)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 52 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 = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1833+1336T>G		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.1833+1336T>G		intron_variant	Intron 24 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108787 AN: 151828 Hom.: 39118 Cov.: 31

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.717 AC: 108899 AN: 151948 Hom.: 39172 Cov.: 31 AF XY: 0.718 AC XY: 53299 AN XY: 74252

African (AFR) AF: 0.729 AC: 30215 AN: 41432

American (AMR) AF: 0.765 AC: 11682 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2447 AN: 3468

East Asian (EAS) AF: 0.634 AC: 3284 AN: 5178

South Asian (SAS) AF: 0.729 AC: 3504 AN: 4804

European-Finnish (FIN) AF: 0.696 AC: 7339 AN: 10544

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48163 AN: 67944

Other (OTH) AF: 0.688 AC: 1447 AN: 2104

Alfa AF: 0.709 Hom.: 62551

Bravo AF: 0.721

Asia WGS AF: 0.724 AC: 2518 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	0.16
DANN	Benign	0.50
PhyloP100		-2.1
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: rs27037; hg19: chr5-96094694;