rs146214639

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L150L) has been classified as Likely benign.

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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

familial pityriasis rubra pilaris
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
psoriasis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001366385.1

BP4

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

BP6

Variant 17-80184012-T-G is Benign according to our data. Variant chr17-80184012-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68781.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1 link	c.449T>G	p.Leu150Arg	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 link	c.449T>G	p.Leu150Arg	missense_variant	Exon 7 of 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

GnomAD2 exomes

AF:

0.00106

AC:

227

AN:

213974

AF XY:

0.00107

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 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

African (AFR)

AF:

0.000363

AC:

AN:

33068

American (AMR)

AF:

0.000754

AC:

AN:

41138

Ashkenazi Jewish (ASJ)

AF:

0.0000394

AC:

AN:

25380

East Asian (EAS)

AF:

0.00

AC:

AN:

38754

South Asian (SAS)

AF:

0.00

AC:

AN:

82628

European-Finnish (FIN)

AF:

0.000331

AC:

AN:

51396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00257

AC:

2820

AN:

1097830

Other (OTH)

AF:

0.00236

AC:

140

AN:

59278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

169

337

506

674

843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00100

AC:

152

AN:

151872

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41390

American (AMR)

AF:

0.000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00184

AC:

125

AN:

67914

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00173

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

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD14: BS1, BS2 -

Inborn genetic diseases

Uncertain:1

Mar 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 04, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CARD14-related disorder

Benign:1

Sep 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.18

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

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over