11-105029808-C-T

Position:

chr11-105029808-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001257118.3(CASP1):c.719G>A(p.Arg240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,682 control chromosomes in the GnomAD database, including 2 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

CASP1
NM_001257118.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.530

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:

LOC124902742 (HGNC:):

LOC124902742 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007607907).

BP6

Variant 11-105029808-C-T is Benign according to our data. Variant chr11-105029808-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041613.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP1	NM_001257118.3 linkuse as main transcript	c.719G>A	p.Arg240Gln	missense_variant	6/9	ENST00000533400.6
LOC124902742	XR_007062869.1 linkuse as main transcript	n.41-1539C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP1	ENST00000533400.6 linkuse as main transcript	c.719G>A	p.Arg240Gln	missense_variant	6/9	1	NM_001257118.3	P2	P29466-1

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

203

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00216

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00135

AC:

340

AN:

251374

Hom.:

AF XY:

0.00141

AC XY:

191

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.00202

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00183

AC:

2674

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1335

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00213

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00133

AC:

202

AN:

152164

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00216

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00186

Hom.:

Bravo

AF:

0.00146

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.00175

EpiControl

AF:

0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CASP1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0097

T;.;.;T;T;.;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.39

T;T;T;.;T;T;T;.;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.0076

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.76

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.46

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T;T;T;T

Polyphen

0.0090, 0.0020, 0.0050, 0.0040, 0.018

.;B;B;B;B;B;B;B;B

Vest4

0.076, 0.16, 0.085, 0.088, 0.13, 0.15, 0.13, 0.095

MVP

0.52

MPC

0.16

ClinPred

0.012

GERP RS

-5.0

Varity_R

0.14

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over