5-96689545-A-T

Variant names:

• chr5-96689545-A-T
• rs149319
• NM_001750.7:c.139-6291A>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.139-6291A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,090 control chromosomes in the GnomAD database, including 12,672 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 0.38 (12672 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.104
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.139-6291A>T		intron_variant	Intron 2 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.139-6291A>T		intron_variant	Intron 2 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57570 AN: 151972 Hom.: 12633 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.366

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

GnomAD4 genome AF: 0.379 AC: 57663 AN: 152090 Hom.: 12672 Cov.: 32 AF XY: 0.381 AC XY: 28314 AN XY: 74344

African (AFR) AF: 0.583 AC: 24191 AN: 41484

American (AMR) AF: 0.419 AC: 6397 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1037 AN: 3470

East Asian (EAS) AF: 0.546 AC: 2827 AN: 5174

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4818

European-Finnish (FIN) AF: 0.256 AC: 2704 AN: 10578

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17577 AN: 67966

Other (OTH) AF: 0.366 AC: 774 AN: 2114

Alfa AF: 0.345 Hom.: 995

Bravo AF: 0.401

Asia WGS AF: 0.442 AC: 1537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.83
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149319; hg19: chr5-96025249; COSMIC: COSV57783699;