NM_001366385.1:c.778G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBS1_SupportingBS2_Supporting

The NM_001366385.1(CARD14):​c.778G>A​(p.Gly260Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,590,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.139

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.041472286).
BS1
Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000025 (36/1438262) while in subpopulation SAS AF = 0.000193 (16/82688). AF 95% confidence interval is 0.000121. There are 0 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 36 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CARD14NM_001366385.1 linkc.778G>A p.Gly260Arg missense_variant Exon 8 of 24 ENST00000648509.2 NP_001353314.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CARD14ENST00000648509.2 linkc.778G>A p.Gly260Arg missense_variant Exon 8 of 24 NM_001366385.1 ENSP00000498071.1 Q9BXL6-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000527
AC:
12
AN:
227574
AF XY:
0.0000809
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000105
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000379
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000250
AC:
36
AN:
1438262
Hom.:
0
Cov.:
31
AF XY:
0.0000294
AC XY:
21
AN XY:
715004
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32210
American (AMR)
AF:
0.0000497
AC:
2
AN:
40254
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25156
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38254
South Asian (SAS)
AF:
0.000193
AC:
16
AN:
82688
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53036
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5656
European-Non Finnish (NFE)
AF:
0.0000145
AC:
16
AN:
1101632
Other (OTH)
AF:
0.0000337
AC:
2
AN:
59376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000197
AC:
3
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41468
American (AMR)
AF:
0.0000654
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000577
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1
Mar 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CARD14 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 565760). This variant has not been reported in the literature in individuals affected with CARD14-related conditions. This variant is present in population databases (rs772988369, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the CARD14 protein (p.Gly260Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
6.7
DANN
Benign
0.38
DEOGEN2
Benign
0.0041
T;T;.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.49
.;.;T;T
M_CAP
Benign
0.0073
T
MetaRNN
Benign
0.041
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;L;L;L
PhyloP100
0.14
PrimateAI
Benign
0.27
T
PROVEAN
Benign
2.2
.;.;.;N
REVEL
Benign
0.032
Sift
Benign
0.61
.;.;.;T
Sift4G
Benign
0.76
T;.;T;T
Polyphen
0.13
B;B;.;B
Vest4
0.10
MutPred
0.13
Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);
MVP
0.26
MPC
0.19
ClinPred
0.020
T
GERP RS
-2.5
Varity_R
0.040
gMVP
0.16
Mutation Taster
=97/3
polymorphism

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

Other links and lift over

dbSNP: rs772988369; hg19: chr17-78162278; COSMIC: COSV107424505; COSMIC: COSV107424505; API