rs387907240

Variant names:

• chr17-80184030-T-C
• rs387907240
• NM_001366385.1:c.467T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001366385.1(CARD14):​c.467T>C​(p.Leu156Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 3.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80184030-T-C is Pathogenic according to our data. Variant chr17-80184030-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35573.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.467T>C	p.Leu156Pro	missense_variant	Exon 7 of 24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.467T>C	p.Leu156Pro	missense_variant	Exon 7 of 24		NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pityriasis rubra pilaris Pathogenic:1 Uncertain:1

Feb 15, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015) -

Jul 13, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Papulosquamous eruptions Pathogenic:1

Mar 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Pathogenic:1

Jun 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 156 of the CARD14 protein (p.Leu156Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CARD14-related conditions (PMID: 22703878, 29477734). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35573). Experimental studies have shown that this variant affects CARD14 protein function (PMID: 25734815, 26203641). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Feb 28, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest this variant results in increased NF-kB activation, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 26203641, 25734815); This variant is associated with the following publications: (PMID: 30319628, 36174714, 28421071, 24577624, 26203641, 25734815, 35262907, 38375322, 36699196, 26130407, 36012602, 29477734, 22703878, 30386326, 32958760) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	.;.;T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.1	M;M;M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	.;.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Uncertain	0.0030	D;.;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.88
MutPred		0.42		Loss of stability (P = 0.0518);Loss of stability (P = 0.0518);Loss of stability (P = 0.0518);Loss of stability (P = 0.0518);
MVP		0.96
MPC		0.83
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.92
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs387907240; hg19: chr17-78157829;