NM_001750.7:c.168A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001750.7(CAST):c.168A>G(p.Gln56Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,608,786 control chromosomes in the GnomAD database, including 34,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2742 hom., cov: 31)

Exomes 𝑓: 0.20 ( 31447 hom. )

Consequence

CAST
NM_001750.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.01

Publications

22 publications found

Variant links:

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 links:

CAST (HGNC:):

CAST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.022).

BP6

Variant 5-96695865-A-G is Benign according to our data. Variant chr5-96695865-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7 link	c.168A>G	p.Gln56Gln	synonymous_variant	Exon 3 of 32	ENST00000675179.1	NP_001741.4	P20810-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1 link	c.168A>G	p.Gln56Gln	synonymous_variant	Exon 3 of 32		NM_001750.7	ENSP00000501872.1		P20810-6

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28353

AN:

151990

Hom.:

2739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.202

Gnomad OTH

AF:

0.174

GnomAD2 exomes

AF:

0.211

AC:

52378

AN:

247922

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.254

Gnomad NFE exome

AF:

0.209

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.205

AC:

298314

AN:

1456678

Hom.:

31447

Cov.:

AF XY:

0.206

AC XY:

149102

AN XY:

724680

show subpopulations

African (AFR)

AF:

0.123

AC:

4107

AN:

33386

American (AMR)

AF:

0.232

AC:

10289

AN:

44410

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

3512

AN:

26050

East Asian (EAS)

AF:

0.261

AC:

10331

AN:

39572

South Asian (SAS)

AF:

0.221

AC:

18965

AN:

85772

European-Finnish (FIN)

AF:

0.254

AC:

13543

AN:

53224

Middle Eastern (MID)

AF:

0.153

AC:

878

AN:

5748

European-Non Finnish (NFE)

AF:

0.203

AC:

224871

AN:

1108312

Other (OTH)

AF:

0.196

AC:

11818

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

10336

20672

31008

41344

51680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7792

15584

23376

31168

38960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.186

AC:

28360

AN:

152108

Hom.:

2742

Cov.:

AF XY:

0.190

AC XY:

14144

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.132

AC:

5458

AN:

41490

American (AMR)

AF:

0.210

AC:

3204

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

451

AN:

3466

East Asian (EAS)

AF:

0.234

AC:

1211

AN:

5182

South Asian (SAS)

AF:

0.226

AC:

1090

AN:

4820

European-Finnish (FIN)

AF:

0.257

AC:

2713

AN:

10562

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.202

AC:

13731

AN:

67980

Other (OTH)

AF:

0.173

AC:

366

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1169

2338

3507

4676

5845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.198

Hom.:

12920

Bravo

AF:

0.179

Asia WGS

AF:

0.259

AC:

901

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.193

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.59

PhyloP100

-1.0

PromoterAI

0.0023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over