rs281875220
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting
The NM_001366385.1(CARD14):c.1778T>A(p.Ile593Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
CARD14
NM_001366385.1 missense
NM_001366385.1 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 3.90
Genes affected
CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BS2
High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARD14 | NM_001366385.1 | c.1778T>A | p.Ile593Asn | missense_variant | 16/24 | ENST00000648509.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CARD14 | ENST00000648509.2 | c.1778T>A | p.Ile593Asn | missense_variant | 16/24 | NM_001366385.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250306Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135516
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460928Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726800
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with psoriasis and in unaffected controls in published literature (Jordan et al., 2012); This variant is associated with the following publications: (PMID: 27939769, 30386326, 22521419) - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pityriasis rubra pilaris Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 29, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. - |
Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 08, 2023 | This variant is present in population databases (rs281875220, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 593 of the CARD14 protein (p.Ile593Asn). This missense change has been observed in individual(s) with psoriasis (PMID: 22521419). 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. Experimental studies have shown that this missense change does not substantially affect CARD14 function (PMID: 22421419). 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 CARD14 protein function. ClinVar contains an entry for this variant (Variation ID: 68776). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;.;D
REVEL
Uncertain
Sift
Benign
.;.;.;T
Sift4G
Pathogenic
D;.;D;D
Polyphen
D;D;.;D
Vest4
MutPred
Loss of stability (P = 0.0379);Loss of stability (P = 0.0379);Loss of stability (P = 0.0379);Loss of stability (P = 0.0379);
MVP
MPC
ClinPred
D
GERP RS
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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