17-80181466-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS2_Supporting

The NM_001366385.1(CARD14):ā€‹c.28G>Cā€‹(p.Ala10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,429,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000035 ( 0 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.435
Variant links:
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 -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06016594).
BS2
High AC in GnomAdExome4 at 5 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 rank MANE Protein UniProt
CARD14NM_001366385.1 linkc.28G>C p.Ala10Pro missense_variant Exon 5 of 24 ENST00000648509.2 NP_001353314.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CARD14ENST00000648509.2 linkc.28G>C p.Ala10Pro missense_variant Exon 5 of 24 NM_001366385.1 ENSP00000498071.1 Q9BXL6-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000350
AC:
5
AN:
1429948
Hom.:
0
Cov.:
32
AF XY:
0.00000565
AC XY:
4
AN XY:
708438
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000365
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1
Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 10 of the CARD14 protein (p.Ala10Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CARD14-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CARD14 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
0.12
DANN
Benign
0.89
DEOGEN2
Benign
0.081
T;T;T;.;.;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.058
N
LIST_S2
Benign
0.66
.;.;.;T;T;T
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.060
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
.;L;L;.;L;L
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.5
.;.;.;.;.;N
REVEL
Benign
0.051
Sift
Benign
0.10
.;.;.;.;.;T
Sift4G
Benign
0.073
T;T;.;T;T;T
Polyphen
0.17
.;B;B;.;.;B
Vest4
0.10, 0.097
MutPred
0.14
Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);
MVP
0.62
MPC
0.37
ClinPred
0.089
T
GERP RS
-8.5
Varity_R
0.090
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78155265; API