Genetic Variant NM_001366385.1:c.1789C>T (chr17-80198529-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001366385.1(CARD14):c.1789C>T(p.Arg597Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,262 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R597L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 31 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.928

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062526762).

BP6

Variant 17-80198529-C-T is Benign according to our data. Variant chr17-80198529-C-T is described in ClinVar as Benign. ClinVar VariationId is 458090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1576/152376) while in subpopulation AFR AF = 0.0361 (1502/41584). AF 95% confidence interval is 0.0346. There are 19 homozygotes in GnomAd4. There are 764 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1576 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366385.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CARD14	NM_001366385.1	MANE Select	c.1789C>T	p.Arg597Trp	missense	Exon 16 of 24	NP_001353314.1
CARD14	NM_024110.4		c.1789C>T	p.Arg597Trp	missense	Exon 13 of 21	NP_077015.2
CARD14	NM_001257970.1		c.1789C>T	p.Arg597Trp	missense	Exon 13 of 15	NP_001244899.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CARD14	ENST00000648509.2	MANE Select	c.1789C>T	p.Arg597Trp	missense	Exon 16 of 24	ENSP00000498071.1
CARD14	ENST00000344227.6	TSL:1	c.1789C>T	p.Arg597Trp	missense	Exon 13 of 21	ENSP00000344549.2
CARD14	ENST00000570421.5	TSL:1	c.1789C>T	p.Arg597Trp	missense	Exon 13 of 15	ENSP00000461806.1

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1575

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00287

AC:

716

AN:

249616

AF XY:

0.00220

show subpopulations

Gnomad AFR exome

AF:

0.0381

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000801

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00104

AC:

1524

AN:

1460886

Hom.:

Cov.:

AF XY:

0.000901

AC XY:

655

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.0366

AC:

1226

AN:

33476

American (AMR)

AF:

0.00212

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52610

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000522

AC:

AN:

1111880

Other (OTH)

AF:

0.00214

AC:

129

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.0103

AC:

1576

AN:

152376

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

764

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0361

AC:

1502

AN:

41584

American (AMR)

AF:

0.00340

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00464

Hom.:

Bravo

AF:

0.0124

ESP6500AA

AF:

0.0363

AC:

160

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00340

AC:

413

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD14: BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Pityriasis rubra pilaris;C1864497:Psoriasis 2

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autoinflammatory syndrome

Benign:1

Feb 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.030

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.8

PhyloP100

0.93

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.28

Sift

Benign

0.29

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.58

MVP

0.87

MPC

0.64

ClinPred

0.035

GERP RS

2.8

Varity_R

0.12

gMVP

0.43

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over