Genetic Variant CASP1:p.Ile328Val (chr11-105029148-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001257118.3(CASP1):c.982A>G(p.Ile328Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I328F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CASP1
NM_001257118.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.78

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35397333).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257118.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP1	NM_001257118.3	MANE Select	c.982A>G	p.Ile328Val	missense	Exon 7 of 9	NP_001244047.1	P29466-1
CASP1	NM_033292.4		c.982A>G	p.Ile328Val	missense	Exon 7 of 10	NP_150634.1	P29466-1
CASP1	NM_001223.5		c.919A>G	p.Ile307Val	missense	Exon 6 of 9	NP_001214.1	P29466-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP1	ENST00000533400.6	TSL:1 MANE Select	c.982A>G	p.Ile328Val	missense	Exon 7 of 9	ENSP00000433138.1	P29466-1
CASP1	ENST00000436863.7	TSL:1	c.982A>G	p.Ile328Val	missense	Exon 7 of 10	ENSP00000410076.3	P29466-1
CASP1	ENST00000526568.5	TSL:1	c.703A>G	p.Ile235Val	missense	Exon 6 of 9	ENSP00000434250.1	P29466-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Benign

0.13

Eigen_PC

Benign

0.062

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

M_CAP

Benign

0.0079

MetaRNN

Benign

0.35

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

2.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.86

REVEL

Benign

0.11

Sift

Benign

0.041

Sift4G

Benign

0.13

Polyphen

0.94

Vest4

0.15

MutPred

0.66

Loss of sheet (P = 0.0817)

MVP

0.65

MPC

0.53

ClinPred

0.85

GERP RS

2.0

Varity_R

0.39

gMVP

0.31

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over