rs571517554
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate
The NM_032415.7(CARD11):c.368G>A(p.Gly123Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,030 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G123S) has been classified as Pathogenic.
Frequency
Consequence
NM_032415.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARD11 | NM_032415.7 | c.368G>A | p.Gly123Asp | missense_variant | 5/25 | ENST00000396946.9 | |
CARD11 | NM_001324281.3 | c.368G>A | p.Gly123Asp | 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.368G>A | p.Gly123Asp | missense_variant | 5/25 | 1 | NM_032415.7 | P1 | |
CARD11-AS1 | ENST00000423194.1 | n.474+20C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459684Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725896
GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74500
ClinVar
Submissions by phenotype
BENTA disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 29, 2014 | - - |
Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This variant disrupts the p.Gly123 amino acid residue in CARD11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23129749, 26861442, 29472930). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CARD11 function (PMID: 23149938, 25352053). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 183144). This missense change has been observed in individual(s) with autosomal dominant B-cell expansion with NFKB and T-cell anergy (BENTA) (PMID: 25352053). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs571517554, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 123 of the CARD11 protein (p.Gly123Asp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at