chr19-48211933-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001184900.3(CARD8):​c.1391G>T​(p.Arg464Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CARD8
NM_001184900.3 missense

Scores

2
3
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
CARD8 (HGNC:17057): (caspase recruitment domain family member 8) The protein encoded by this gene belongs to the caspase recruitment domain (CARD)-containing family of proteins, which are involved in pathways leading to activation of caspases or nuclear factor kappa-B (NFKB). This protein may be a component of the inflammasome, a protein complex that plays a role in the activation of proinflammatory caspases. It is thought that this protein acts as an adaptor molecule that negatively regulates NFKB activation, CASP1-dependent IL1B secretion, and apoptosis. Polymorphisms in this gene may be associated with a susceptibility to rheumatoid arthritis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a mutagenesis_site Abolished formation of inflammasome filaments. Abolished ability to induce pyroptosis. (size 0) in uniprot entity CARD8_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27540913).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CARD8NM_001184900.3 linkuse as main transcriptc.1391G>T p.Arg464Met missense_variant 14/14 ENST00000651546.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CARD8ENST00000651546.1 linkuse as main transcriptc.1391G>T p.Arg464Met missense_variant 14/14 NM_001184900.3 A2Q9Y2G2-5
ENST00000595201.2 linkuse as main transcriptn.390-1033C>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461842
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 26, 2023The c.1391G>T (p.R464M) alteration is located in exon 11 (coding exon 11) of the CARD8 gene. This alteration results from a G to T substitution at nucleotide position 1391, causing the arginine (R) at amino acid position 464 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
19
DANN
Benign
0.94
Eigen
Benign
-0.089
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.57
T;T;.;.;.
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.28
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.3
D;D;D;D;D
REVEL
Benign
0.18
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Vest4
0.46
MVP
0.18
MPC
0.69
ClinPred
0.90
D
GERP RS
2.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1413699040; hg19: chr19-48715190; COSMIC: COSV105913589; COSMIC: COSV105913589; API