Genetic Variant CARD14:p.Pro506Leu (chr17-80195575-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.1517C>T(p.Pro506Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,612,032 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P506R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 33)

Exomes 𝑓: 0.015 ( 257 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0430

Publications

11 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
psoriasis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

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=0.0025039911).

BP6

Variant 17-80195575-C-T is Benign according to our data. Variant chr17-80195575-C-T is described in ClinVar as Benign. ClinVar VariationId is 458088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0107 (1622/152266) while in subpopulation SAS AF = 0.0455 (219/4812). AF 95% confidence interval is 0.0406. There are 16 homozygotes in GnomAd4. There are 763 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1622 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	UniProt
CARD14	NM_001366385.1	MANE Select	c.1517C>T	p.Pro506Leu	missense	Exon 14 of 24	NP_001353314.1	Q9BXL6-1
CARD14	NM_024110.4		c.1517C>T	p.Pro506Leu	missense	Exon 11 of 21	NP_077015.2	Q9BXL6-1
CARD14	NM_001257970.1		c.1517C>T	p.Pro506Leu	missense	Exon 11 of 15	NP_001244899.1	Q9BXL6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARD14	ENST00000648509.2	MANE Select	c.1517C>T	p.Pro506Leu	missense	Exon 14 of 24	ENSP00000498071.1	Q9BXL6-1
CARD14	ENST00000344227.6	TSL:1	c.1517C>T	p.Pro506Leu	missense	Exon 11 of 21	ENSP00000344549.2	Q9BXL6-1
CARD14	ENST00000570421.5	TSL:1	c.1517C>T	p.Pro506Leu	missense	Exon 11 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1623

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0455

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0137

AC:

3365

AN:

245954

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.00273

Gnomad AMR exome

AF:

0.00545

Gnomad ASJ exome

AF:

0.00455

Gnomad EAS exome

AF:

0.000547

Gnomad FIN exome

AF:

0.00559

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0147

AC:

21460

AN:

1459766

Hom.:

257

Cov.:

AF XY:

0.0155

AC XY:

11249

AN XY:

726174

show subpopulations

African (AFR)

AF:

0.00341

AC:

114

AN:

33468

American (AMR)

AF:

0.00576

AC:

257

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00421

AC:

110

AN:

26110

East Asian (EAS)

AF:

0.000403

AC:

AN:

39688

South Asian (SAS)

AF:

0.0441

AC:

3801

AN:

86128

European-Finnish (FIN)

AF:

0.00624

AC:

325

AN:

52042

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0143

AC:

15910

AN:

1111620

Other (OTH)

AF:

0.0146

AC:

883

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1016

2032

3048

4064

5080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.0107

AC:

1622

AN:

152266

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

763

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00371

AC:

154

AN:

41556

American (AMR)

AF:

0.00738

AC:

113

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.0455

AC:

219

AN:

4812

European-Finnish (FIN)

AF:

0.00555

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0153

AC:

1039

AN:

67994

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

182

274

365

456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0128

Hom.:

Bravo

AF:

0.00911

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.0144

AC:

1752

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0107

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoinflammatory syndrome (1)

not provided (1)

Pityriasis rubra pilaris;C1864497:Psoriasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.73

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0045

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

PhyloP100

-0.043

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.72

REVEL

Benign

0.046

Sift

Benign

0.12

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.034

MPC

0.15

ClinPred

0.0013

GERP RS

1.4

Varity_R

0.027

gMVP

0.12

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over