rs387907352
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_032415.7(CARD11):c.367G>A(p.Gly123Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G123D) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CARD11
NM_032415.7 missense
NM_032415.7 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 5.47
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 Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_032415.7
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr7-2944528-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 183144.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, CARD11
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.885
PP5
?
Variant 7-2944529-C-T is Pathogenic according to our data. Variant chr7-2944529-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 48648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2944529-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARD11 | NM_032415.7 | c.367G>A | p.Gly123Ser | missense_variant | 5/25 | ENST00000396946.9 | |
CARD11 | NM_001324281.3 | c.367G>A | p.Gly123Ser | missense_variant | 6/26 | ||
CARD11-AS1 | XR_926993.2 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CARD11 | ENST00000396946.9 | c.367G>A | p.Gly123Ser | missense_variant | 5/25 | 1 | NM_032415.7 | P1 | |
CARD11-AS1 | ENST00000423194.1 | n.474+21C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459628Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725874
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1459628
Hom.:
Cov.:
30
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AC XY:
0
AN XY:
725874
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ExAC
?
AF:
AC:
1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
BENTA disease Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 19, 2012 | - - |
Pathogenic, no assertion criteria provided | literature only | Molecular Diagnosis for Inborn Errors of Immunity, Hospital de Pediatria Garrahan | - | The Gly123Ser variant in CARD11 has been reported in BENTA patients (Meitlis et al 2020 Am J Hum Genetics, Ma CA et al 2017 Nature Genetics, Snow AL et al 2012 J Exp Med) and was absent from large population studies. Additionally, in vitro functional studies indicate that the Gly123Ser variant significantly increased NF-kB reporter signal, either with or without stimulation by anti-CD3/CD28 antibodies (Meitlis et al 2020 Am J Hum Genetics, Ma CA et al 2017 Nature Genetics). - |
Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly123 amino acid residue in CARD11. Other variant(s) that disrupt this residue have been observed in individuals with CARD11-related conditions (PMID: 25352053, 28824638), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 123 of the CARD11 protein (p.Gly123Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant B-cell expansion with NFKB and T-cell anergy (BENTA) (PMID: 23129749, 26861442, 29472930). In at least one individual the variant was observed to be de novo. This variant is also known as G116S. ClinVar contains an entry for this variant (Variation ID: 48648). 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) performed at Invitae indicates that this missense variant is expected to disrupt CARD11 protein function. Experimental studies have shown that this missense change affects CARD11 function (PMID: 23027925, 23129749, 25352053). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | CARD11: PM1, PM2, PP4:Moderate, PS3:Moderate, PS4:Moderate, PP2 - |
Asthma;C0029453:Osteopenia;C0038002:Splenomegaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 06, 2021 | ACMG classification criteria: PS4 strong, PM2 moderate, PM5, PM6 moderate, PP2 supporting, BP4 supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Benign
T
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at G123 (P = 0.0884);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at