rs11652075

chr17-80205094-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001366385.1(CARD14):c.2458C>T(p.Arg820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 1,612,294 control chromosomes in the GnomAD database, including 183,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13113 hom., cov: 33)
  • Exomes 𝑓: 0.48 (170694 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:7 O:1
• Conservation: PhyloP100: 2.56

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8051267E-4).
• BP6: Variant 17-80205094-C-T is Benign according to our data. Variant chr17-80205094-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402487.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, not_provided=1, Likely_pathogenic=1}. Variant chr17-80205094-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.2458C>T	p.Arg820Trp	missense_variant	21/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.2458C>T	p.Arg820Trp	missense_variant	21/24		NM_001366385.1	P1
	ENST00000570309.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60778 AN: 151996 Hom.: 13115 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.402

GnomAD3 exomes AF: 0.414 AC: 102372 AN: 247554 Hom.: 22358 AF XY: 0.421 AC XY: 56483 AN XY: 134228

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.468

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.477 AC: 697129 AN: 1460180 Hom.: 170694 Cov.: 46 AF XY: 0.474 AC XY: 344601 AN XY: 726394

Gnomad4 AFR exome AF: 0.232

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.547

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.400 AC: 60777 AN: 152114 Hom.: 13113 Cov.: 33 AF XY: 0.395 AC XY: 29401 AN XY: 74358

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.495

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.402

Alfa AF: 0.474 Hom.: 36997

Bravo AF: 0.385

TwinsUK AF: 0.504 AC: 1867

ALSPAC AF: 0.519 AC: 2001

ESP6500AA AF: 0.249 AC: 1095

ESP6500EA AF: 0.492 AC: 4227

ExAC AF: 0.414 AC: 50234

Asia WGS AF: 0.383 AC: 1333 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pityriasis rubra pilaris Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	Feb 21, 2024	CARD14 is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Potent mutations in Card14 have been shown to be associated with familial pustular psoriasis and other cutaneous inflammatory conditions like Pytriasis rubra pilaris. Sufficient evidence is found to confer the association of this particular variant rs11652075 with psoriasis.This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 20.9 and sufficient scientific evidence to support the reported classification. This is found more frequently in psoriasis as per recent evidence as well. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 60% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 27706581, 26249641, 31994212, 23905699, 26854129, 30018619, 23143594) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.57	D
MetaRNN	Benign	0.00018	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.035	D;.;D
Polyphen		0.91	P;P;P
Vest4		0.11
MPC		0.37
ClinPred		0.028	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.073
gMVP		0.69

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

Other links and lift over

dbSNP: rs11652075; hg19: chr17-78178893;