17-80182790-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP5_Moderate
The NM_001366385.1(CARD14):c.349G>A(p.Gly117Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
CARD14
NM_001366385.1 missense, splice_region
NM_001366385.1 missense, splice_region
Scores
5
10
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.88
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001366385.1
PP5
?
Variant 17-80182790-G-A is Pathogenic according to our data. Variant chr17-80182790-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31606.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-80182790-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CARD14 | NM_001366385.1 | c.349G>A | p.Gly117Ser | missense_variant, splice_region_variant | 6/24 | ENST00000648509.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CARD14 | ENST00000648509.2 | c.349G>A | p.Gly117Ser | missense_variant, splice_region_variant | 6/24 | NM_001366385.1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251282Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135804
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461850Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727232
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Psoriasis 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2013 | - - |
Papulosquamous eruptions Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Mar 01, 2018 | - - |
Pityriasis rubra pilaris;C1864497:Psoriasis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 117 of the CARD14 protein (p.Gly117Ser). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs281875215, gnomAD 0.003%). This missense change has been observed in individual(s) with CARD14-related disorders (PMID: 22521418, 22521419, 29477734). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31606). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CARD14 function (PMID: 22521418, 22521419). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 22521418). For these reasons, this variant has been classified as Pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;.;T;T
Polyphen
D;D;.;D
Vest4
MutPred
Gain of disorder (P = 0.0581);Gain of disorder (P = 0.0581);Gain of disorder (P = 0.0581);Gain of disorder (P = 0.0581);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at