rs281875218

Positions:

chr17-80184134-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366385.1(CARD14):c.571G>T(p.Val191Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,569,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 2.28

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]

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11231667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1 linkuse as main transcript	c.571G>T	p.Val191Leu	missense_variant	7/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2 linkuse as main transcript	c.571G>T	p.Val191Leu	missense_variant	7/24		NM_001366385.1	P1	Q9BXL6-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000561

AC:

AN:

178360

Hom.:

AF XY:

0.0000105

AC XY:

AN XY:

95102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1417752

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700986

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:

0.00000275

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2021

This sequence change replaces valine with leucine at codon 191 of the CARD14 protein (p.Val191Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with psoriasis (PMID: 22521419). ClinVar contains an entry for this variant (Variation ID: 68784). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CARD14 function (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. -

not provided

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.17

DEOGEN2

Benign

0.0081

T;T;.;T

Eigen

Benign

0.046

Eigen_PC

Benign

-0.0092

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.67

.;.;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;L;L

MutationTaster

Benign

0.64

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

1.1

.;.;.;N

REVEL

Benign

0.12

Sift

Benign

1.0

.;.;.;T

Sift4G

Benign

0.28

T;.;T;T

Polyphen

0.98

D;D;.;D

Vest4

0.12

MutPred

0.28

Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);

MVP

0.57

MPC

0.17

ClinPred

0.26

GERP RS

3.6

Varity_R

0.059

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over