rs146214639

Positions:

chr17-80184012-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001366385.1(CARD14):c.449T>G(p.Leu150Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,587,026 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: 0.182

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:

CARD14 (HGNC:):

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009278655).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.001 (152/151872) while in subpopulation NFE AF= 0.00184 (125/67914). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD14	NM_001366385.1 linkuse as main transcript	c.449T>G	p.Leu150Arg	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 linkuse as main transcript	c.449T>G	p.Leu150Arg	missense_variant	7/24		NM_001366385.1	ENSP00000498071.1		Q9BXL6-1

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

152

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00106

AC:

227

AN:

213974

Hom.:

AF XY:

0.00107

AC XY:

124

AN XY:

116304

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000772

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000166

Gnomad NFE exome

AF:

0.00195

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00211

AC:

3021

AN:

1435154

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

1443

AN XY:

710568

show subpopulations

Gnomad4 AFR exome

AF:

0.000363

Gnomad4 AMR exome

AF:

0.000754

Gnomad4 ASJ exome

AF:

0.0000394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000331

Gnomad4 NFE exome

AF:

0.00257

Gnomad4 OTH exome

AF:

0.00236

GnomAD4 genome

AF:

0.00100

AC:

152

AN:

151872

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00104

AC:

126

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Feb 08, 2022	This variant has not been reported in the literature but is present in 0.1% (125/67922) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-80184012-T-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:68781). This variant amino acid Arginine (Arg) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CARD14: BS1, BS2 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The c.449T>G (p.L150R) alteration is located in exon 4 (coding exon 3) of the CARD14 gene. This alteration results from a T to G substitution at nucleotide position 449, causing the leucine (L) at amino acid position 150 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 04, 2017

- -

CARD14-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.0

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

T;T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.56

.;.;T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

M;M;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

.;.;.;N

REVEL

Benign

0.069

Sift

Uncertain

0.0050

.;.;.;D

Sift4G

Uncertain

0.0070

D;.;D;D

Polyphen

0.89

P;P;.;P

Vest4

0.22

MVP

0.73

MPC

0.24

ClinPred

0.041

GERP RS

-2.8

Varity_R

0.30

gMVP

0.49

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

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