rs775267971
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_052813.5(CARD9):c.68C>T(p.Ser23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,678 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 1 hom., cov: 34)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
CARD9
NM_052813.5 missense
NM_052813.5 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 2.12
Genes affected
CARD9 (HGNC:16391): (caspase recruitment domain family member 9) The protein encoded by this gene is a member of the CARD protein family, which is defined by the presence of a characteristic caspase-associated recruitment domain (CARD). CARD is a protein interaction domain known to participate in activation or suppression of CARD containing members of the caspase family, and thus plays an important regulatory role in cell apoptosis. This protein was identified by its selective association with the CARD domain of BCL10, a postive regulator of apoptosis and NF-kappaB activation, and is thought to function as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-kappaB. Several alternatively spliced transcript variants have been observed, but their full-length nature is not clearly defined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a domain CARD (size 92) in uniprot entity CARD9_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_052813.5
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARD9 | NM_052813.5 | c.68C>T | p.Ser23Leu | missense_variant | 2/13 | ENST00000371732.10 | |
CARD9 | NM_052814.4 | c.68C>T | p.Ser23Leu | missense_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CARD9 | ENST00000371732.10 | c.68C>T | p.Ser23Leu | missense_variant | 2/13 | 1 | NM_052813.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152192Hom.: 1 Cov.: 34
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250352Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135702
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460486Hom.: 0 Cov.: 82 AF XY: 0.00000963 AC XY: 7AN XY: 726532
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152192Hom.: 1 Cov.: 34 AF XY: 0.0000538 AC XY: 4AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Predisposition to invasive fungal disease due to CARD9 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CARD9-related disease. This variant is present in population databases (rs775267971, ExAC 0.006%). This sequence change replaces serine with leucine at codon 23 of the CARD9 protein (p.Ser23Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Loss of disorder (P = 0.2002);Loss of disorder (P = 0.2002);
MVP
MPC
1.5
ClinPred
D
GERP RS
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