rs7724759

Variant names:

• chr5-96740783-G-A
• rs7724759
• NM_001750.7:c.918G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001750.7(CAST):​c.918G>A​(p.Ser306Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,575,622 control chromosomes in the GnomAD database, including 70,217 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S306S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (4989 hom., cov: 32)
  • Exomes 𝑓: 0.29 (65228 hom.)
• Consequence: CAST NM_001750.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• Publications: 28 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 5-96740783-G-A is Benign according to our data. Variant chr5-96740783-G-A is described in ClinVar as Benign. ClinVar VariationId is 1274351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 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.918G>A	p.Ser306Ser	splice_region synonymous	Exon 13 of 32	NP_001741.4
	CAST	NM_001042441.3		c.861G>A	p.Ser287Ser	splice_region synonymous	Exon 12 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.852G>A	p.Ser284Ser	splice_region synonymous	Exon 12 of 31	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.918G>A	p.Ser306Ser	splice_region synonymous	Exon 13 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.669G>A	p.Ser223Ser	splice_region synonymous	Exon 11 of 30	ENSP00000339914.3
	CAST	ENST00000309190.9	TSL:1	c.603G>A	p.Ser201Ser	splice_region synonymous	Exon 10 of 29	ENSP00000312523.5

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35971 AN: 151908 Hom.: 4987 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.248 AC: 62042 AN: 250004 AF XY: 0.256

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.0802

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.293 AC: 417564 AN: 1423596 Hom.: 65228 Cov.: 25 AF XY: 0.293 AC XY: 208330 AN XY: 710198

African (AFR) AF: 0.101 AC: 3325 AN: 32938

American (AMR) AF: 0.176 AC: 7851 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7856 AN: 25852

East Asian (EAS) AF: 0.0762 AC: 3014 AN: 39540

South Asian (SAS) AF: 0.231 AC: 19704 AN: 85326

European-Finnish (FIN) AF: 0.269 AC: 14352 AN: 53350

Middle Eastern (MID) AF: 0.289 AC: 1645 AN: 5694

European-Non Finnish (NFE) AF: 0.319 AC: 343196 AN: 1077320

Other (OTH) AF: 0.281 AC: 16621 AN: 59072

GnomAD4 genome AF: 0.237 AC: 35984 AN: 152026 Hom.: 4989 Cov.: 32 AF XY: 0.233 AC XY: 17301 AN XY: 74286

African (AFR) AF: 0.107 AC: 4436 AN: 41458

American (AMR) AF: 0.217 AC: 3312 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3470

East Asian (EAS) AF: 0.0744 AC: 384 AN: 5164

South Asian (SAS) AF: 0.217 AC: 1047 AN: 4820

European-Finnish (FIN) AF: 0.275 AC: 2908 AN: 10556

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.323 AC: 21947 AN: 67958

Other (OTH) AF: 0.252 AC: 532 AN: 2112

Alfa AF: 0.284 Hom.: 16409

Bravo AF: 0.227

Asia WGS AF: 0.167 AC: 578 AN: 3478

EpiCase AF: 0.320

EpiControl AF: 0.325

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.72
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 0

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

Other links and lift over

dbSNP: rs7724759; hg19: chr5-96076487; COSMIC: COSV57783359; COSMIC: COSV57783359;