rs1559085

Variant names:

• chr5-96742998-A-G
• rs1559085
• NM_001750.7:c.1200+242A>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.1200+242A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.094 in 152,280 control chromosomes in the GnomAD database, including 879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.094 (879 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.58
• Publications: 18 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, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-96742998-A-G is Benign according to our data. Variant chr5-96742998-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266205.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.1200+242A>G		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.1143+242A>G		intron	N/A	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.1134+242A>G		intron	N/A	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.1200+242A>G		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.951+242A>G		intron	N/A	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.912+242A>G		intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14318 AN: 152162 Hom.: 879 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0787

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.0940 AC: 14316 AN: 152280 Hom.: 879 Cov.: 32 AF XY: 0.0940 AC XY: 7001 AN XY: 74466

African (AFR) AF: 0.0230 AC: 956 AN: 41568

American (AMR) AF: 0.101 AC: 1539 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0792 AC: 382 AN: 4824

European-Finnish (FIN) AF: 0.132 AC: 1396 AN: 10602

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.136 AC: 9254 AN: 68008

Other (OTH) AF: 0.121 AC: 256 AN: 2110

Alfa AF: 0.126 Hom.: 2122

Bravo AF: 0.0887

Asia WGS AF: 0.0320 AC: 113 AN: 3478

ClinVar

ClinVar submissions

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	-0.82
CADD	Benign	0.17
DANN	Benign	0.55
PhyloP100		-1.6
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: rs1559085; hg19: chr5-96078702; COSMIC: COSV57784030; COSMIC: COSV57784030;