Genetic Variant NM_001257118.3:c.766C>T (chr11-105029761-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001257118.3(CASP1):c.766C>T(p.Leu256Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,612,946 control chromosomes in the GnomAD database, including 23,608 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.15 ( 2029 hom., cov: 32)

Exomes 𝑓: 0.16 ( 21579 hom. )

Consequence

CASP1
NM_001257118.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.744

Publications

29 publications found

Variant links:

Genes affected

CASP1 (HGNC:1499): (caspase 1) This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce 2 subunits, large and small, that dimerize to form the active enzyme. This gene was identified by its ability to proteolytically cleave and activate the inactive precursor of interleukin-1, a cytokine involved in the processes such as inflammation, septic shock, and wound healing. This gene has been shown to induce cell apoptosis and may function in various developmental stages. Studies of a similar gene in mouse suggest a role in the pathogenesis of Huntington disease. Alternative splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

CASP1 links:

ENSG00000303891 (HGNC:):

ENSG00000303891 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP7

Synonymous conserved (PhyloP=0.744 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP1	NM_001257118.3 link	c.766C>T	p.Leu256Leu	synonymous_variant	Exon 6 of 9	ENST00000533400.6	NP_001244047.1	P29466-1A8K249

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP1	ENST00000533400.6 link	c.766C>T	p.Leu256Leu	synonymous_variant	Exon 6 of 9	1	NM_001257118.3	ENSP00000433138.1		P29466-1

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23157

AN:

151920

Hom.:

2025

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0978

Gnomad AMI

AF:

0.283

Gnomad AMR

AF:

0.246

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.00425

Gnomad SAS

AF:

0.111

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.161

GnomAD2 exomes

AF:

0.172

AC:

43261

AN:

251230

AF XY:

0.165

show subpopulations

Gnomad AFR exome

AF:

0.0967

Gnomad AMR exome

AF:

0.331

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.00425

Gnomad FIN exome

AF:

0.215

Gnomad NFE exome

AF:

0.171

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.165

AC:

240476

AN:

1460908

Hom.:

21579

Cov.:

AF XY:

0.162

AC XY:

117585

AN XY:

726834

show subpopulations

African (AFR)

AF:

0.0951

AC:

3181

AN:

33438

American (AMR)

AF:

0.319

AC:

14264

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

4408

AN:

26118

East Asian (EAS)

AF:

0.00207

AC:

AN:

39672

South Asian (SAS)

AF:

0.108

AC:

9282

AN:

86250

European-Finnish (FIN)

AF:

0.217

AC:

11569

AN:

53414

Middle Eastern (MID)

AF:

0.115

AC:

662

AN:

5764

European-Non Finnish (NFE)

AF:

0.169

AC:

187954

AN:

1111238

Other (OTH)

AF:

0.150

AC:

9074

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

10589

21178

31766

42355

52944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6670

13340

20010

26680

33350

<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:

0.152

AC:

23183

AN:

152038

Hom.:

2029

Cov.:

AF XY:

0.155

AC XY:

11521

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0982

AC:

4074

AN:

41504

American (AMR)

AF:

0.246

AC:

3753

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

572

AN:

3470

East Asian (EAS)

AF:

0.00445

AC:

AN:

5168

South Asian (SAS)

AF:

0.111

AC:

535

AN:

4824

European-Finnish (FIN)

AF:

0.217

AC:

2294

AN:

10578

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.166

AC:

11300

AN:

67956

Other (OTH)

AF:

0.159

AC:

335

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

983

1967

2950

3934

4917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.161

Hom.:

928

Bravo

AF:

0.155

Asia WGS

AF:

0.0760

AC:

263

AN:

3478

EpiCase

AF:

0.154

EpiControl

AF:

0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.75

(source)

DANN

Benign

0.53

PhyloP100

0.74

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over