chr17-80184030-T-C

Position:

• chr17-80184030-T-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: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.467T>C	p.Leu156Pro	missense_variant	7/24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.467T>C	p.Leu156Pro	missense_variant	7/24		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

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 15, 2021	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) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2012	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects CARD14 protein function (PMID: 25734815, 26203641). 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). This variant is not present in population databases (ExAC no frequency). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2024

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;