NM_001750.7:c.1472G>C

Variant names:

• chr5-96750630-G-C
• rs754615
• NM_001750.7:c.1472G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001750.7(CAST):​c.1472G>C​(p.Cys491Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,610,838 control chromosomes in the GnomAD database, including 115,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9438 hom., cov: 31)
  • Exomes 𝑓: 0.37 (105620 hom.)
• Consequence: CAST NM_001750.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05
• Publications: 49 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022271872).
• BP6: Variant 5-96750630-G-C is Benign according to our data. Variant chr5-96750630-G-C is described in ClinVar as Benign. ClinVar VariationId is 1192697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 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.1472G>C	p.Cys491Ser	missense	Exon 20 of 32	NP_001741.4
	CAST	NM_001042441.3		c.1415G>C	p.Cys472Ser	missense	Exon 19 of 31	NP_001035906.1
	CAST	NM_001042442.3		c.1406G>C	p.Cys469Ser	missense	Exon 19 of 31	NP_001035907.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.1472G>C	p.Cys491Ser	missense	Exon 20 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1223G>C	p.Cys408Ser	missense	Exon 18 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1184G>C	p.Cys395Ser	missense	Exon 19 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52791 AN: 151710 Hom.: 9430 Cov.: 31

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.329 AC: 82412 AN: 250846 AF XY: 0.337

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.375 AC: 546799 AN: 1459010 Hom.: 105620 Cov.: 32 AF XY: 0.376 AC XY: 272665 AN XY: 725814

African (AFR) AF: 0.320 AC: 10698 AN: 33394

American (AMR) AF: 0.217 AC: 9673 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10806 AN: 26076

East Asian (EAS) AF: 0.125 AC: 4965 AN: 39664

South Asian (SAS) AF: 0.362 AC: 31190 AN: 86170

European-Finnish (FIN) AF: 0.331 AC: 17645 AN: 53320

Middle Eastern (MID) AF: 0.440 AC: 2534 AN: 5754

European-Non Finnish (NFE) AF: 0.394 AC: 437153 AN: 1109694

Other (OTH) AF: 0.367 AC: 22135 AN: 60266

GnomAD4 genome AF: 0.348 AC: 52825 AN: 151828 Hom.: 9438 Cov.: 31 AF XY: 0.344 AC XY: 25551 AN XY: 74202

African (AFR) AF: 0.317 AC: 13105 AN: 41372

American (AMR) AF: 0.292 AC: 4455 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1427 AN: 3468

East Asian (EAS) AF: 0.108 AC: 560 AN: 5170

South Asian (SAS) AF: 0.348 AC: 1678 AN: 4816

European-Finnish (FIN) AF: 0.338 AC: 3563 AN: 10536

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26800 AN: 67902

Other (OTH) AF: 0.336 AC: 706 AN: 2104

Alfa AF: 0.379 Hom.: 8412

Bravo AF: 0.341

TwinsUK AF: 0.399 AC: 1479

ALSPAC AF: 0.394 AC: 1520

ESP6500AA AF: 0.322 AC: 1420

ESP6500EA AF: 0.381 AC: 3278

ExAC AF: 0.334 AC: 40484

Asia WGS AF: 0.258 AC: 896 AN: 3478

EpiCase AF: 0.398

EpiControl AF: 0.401

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.3
DANN	Benign	0.36
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.00050	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	N
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.11
Sift	Benign	0.65	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.022
MutPred		0.31		Gain of sheet (P = 0.0043)
MPC		0.035
ClinPred		0.0069	T
GERP RS		4.5
PromoterAI		-0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.057
gMVP		0.048
Mutation Taster		=99/1	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: rs754615; hg19: chr5-96086334; COSMIC: COSV57783373; COSMIC: COSV57783373;