rs751008087
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_032415.7(CARD11):c.1136G>A(p.Arg379Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
CARD11
NM_032415.7 missense
NM_032415.7 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
CARD11 (HGNC:16393): (caspase recruitment domain family member 11) The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CARD11. . Gene score misZ 3.5439 (greater than the threshold 3.09). Trascript score misZ 3.7177 (greater than threshold 3.09). GenCC has associacion of gene with BENTA disease, immunodeficiency 11b with atopic dermatitis, severe combined immunodeficiency due to CARD11 deficiency.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CARD11 | NM_032415.7 | c.1136G>A | p.Arg379Gln | missense_variant | 8/25 | ENST00000396946.9 | NP_115791.3 | |
CARD11 | NM_001324281.3 | c.1136G>A | p.Arg379Gln | missense_variant | 9/26 | NP_001311210.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CARD11 | ENST00000396946.9 | c.1136G>A | p.Arg379Gln | missense_variant | 8/25 | 1 | NM_032415.7 | ENSP00000380150.4 | ||
CARD11 | ENST00000698637.1 | n.1462G>A | non_coding_transcript_exon_variant | 8/24 | ||||||
CARD11 | ENST00000698654.1 | n.1395G>A | non_coding_transcript_exon_variant | 8/10 | ||||||
CARD11 | ENST00000698662.1 | n.1336G>A | non_coding_transcript_exon_variant | 8/10 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249674Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135100
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GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460852Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726726
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 379 of the CARD11 protein (p.Arg379Gln). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CARD11 protein function. ClinVar contains an entry for this variant (Variation ID: 562203). This variant has not been reported in the literature in individuals affected with CARD11-related conditions. This variant is present in population databases (rs751008087, gnomAD 0.002%). - |
Severe combined immunodeficiency due to CARD11 deficiency;C4539957:Immunodeficiency 11b with atopic dermatitis;C4551967:BENTA disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 07, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at F383 (P = 0.3503);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at