chr17-80205094-C-T

Position:

chr17-80205094-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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).

Frequency

Genomes: 𝑓 0.40 ( 13113 hom., cov: 33)

Exomes 𝑓: 0.48 ( 170694 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:8O:1

Conservation

PhyloP100: 2.56

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 links:

ENSG00000262580 (HGNC:):

ENSG00000262580 links:

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

SGSH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {not_provided=1, Benign=8, 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	Protein	UniProt
CARD14	NM_001366385.1 link	c.2458C>T	p.Arg820Trp	missense_variant	21/24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2 link	c.2458C>T	p.Arg820Trp	missense_variant	21/24		NM_001366385.1	ENSP00000498071.1		Q9BXL6-1

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60778

AN:

151996

Hom.:

13115

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.474

AC XY:

344601

AN XY:

726394

show subpopulations

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.:

AF XY:

0.395

AC XY:

29401

AN XY:

74358

show subpopulations

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:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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) -

Pityriasis rubra pilaris

Pathogenic:1Benign:1

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

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

LIST_S2

Benign

0.82

.;.;T

MetaRNN

Benign

0.00018

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

L;L;L

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.9

.;.;D

REVEL

Benign

0.11

Sift

Uncertain

0.0040

.;.;D

Sift4G

Uncertain

0.035

D;.;D

Polyphen

0.91

P;P;P

Vest4

0.11

MPC

0.37

ClinPred

0.028

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over