rs26503

Variant names:

• chr5-96742605-G-A
• rs26503
• NM_001750.7:c.1099-50G>A

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.1099-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,107,250 control chromosomes in the GnomAD database, including 283,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35610 hom., cov: 31)
  • Exomes 𝑓: 0.72 (248292 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.155
• Publications: 16 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=-0.74).
• BP6: Variant 5-96742605-G-A is Benign according to our data. Variant chr5-96742605-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.759 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.1099-50G>A		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.1042-50G>A		intron	N/A	NP_001035906.1
	CAST	NM_001042442.3		c.1033-50G>A		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.1099-50G>A		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.850-50G>A		intron	N/A	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.811-50G>A		intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103358 AN: 151852 Hom.: 35578 Cov.: 31

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.675

GnomAD2 exomes AF: 0.713 AC: 163908 AN: 229862 AF XY: 0.709

Gnomad AFR exome AF: 0.567

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.623

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.716

GnomAD4 exome AF: 0.718 AC: 685775 AN: 955280 Hom.: 248292 Cov.: 12 AF XY: 0.716 AC XY: 354812 AN XY: 495824

African (AFR) AF: 0.556 AC: 13121 AN: 23614

American (AMR) AF: 0.837 AC: 35583 AN: 42534

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 13801 AN: 22810

East Asian (EAS) AF: 0.686 AC: 25233 AN: 36782

South Asian (SAS) AF: 0.635 AC: 47499 AN: 74796

European-Finnish (FIN) AF: 0.734 AC: 38517 AN: 52456

Middle Eastern (MID) AF: 0.594 AC: 2866 AN: 4826

European-Non Finnish (NFE) AF: 0.733 AC: 478983 AN: 653876

Other (OTH) AF: 0.692 AC: 30172 AN: 43586

GnomAD4 genome AF: 0.681 AC: 103434 AN: 151970 Hom.: 35610 Cov.: 31 AF XY: 0.682 AC XY: 50608 AN XY: 74238

African (AFR) AF: 0.569 AC: 23586 AN: 41420

American (AMR) AF: 0.771 AC: 11772 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2082 AN: 3470

East Asian (EAS) AF: 0.643 AC: 3320 AN: 5162

South Asian (SAS) AF: 0.641 AC: 3078 AN: 4802

European-Finnish (FIN) AF: 0.732 AC: 7729 AN: 10556

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.731 AC: 49668 AN: 67972

Other (OTH) AF: 0.676 AC: 1423 AN: 2106

Alfa AF: 0.700 Hom.: 17711

Bravo AF: 0.680

Asia WGS AF: 0.663 AC: 2309 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.4
DANN	Benign	0.87
PhyloP100		-0.15
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs26503; hg19: chr5-96078309; COSMIC: COSV57785672; COSMIC: COSV57785672;