rs117918077

chr17-80202245-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP4_Strong BS1 BS2

The NM_001366385.1(CARD14):c.2044C>T(p.Arg682Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,026 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (203 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 7.57

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 -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009360939).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0108 (1646/152310) while in subpopulation NFE AF= 0.0167 (1135/68022). AF 95% confidence interval is 0.0159. There are 10 homozygotes in gnomad4. There are 735 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1647 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.2044C>T	p.Arg682Trp	missense_variant	18/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.2044C>T	p.Arg682Trp	missense_variant	18/24		NM_001366385.1	P1
	ENST00000570309.1	n.2827G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1647 AN: 152192 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0111 AC: 2802 AN: 251360 Hom.: 25 AF XY: 0.0114 AC XY: 1547 AN XY: 135900

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00663

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0144 AC: 21075 AN: 1461716 Hom.: 203 Cov.: 32 AF XY: 0.0144 AC XY: 10460 AN XY: 727156

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00621

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0108 AC: 1646 AN: 152310 Hom.: 10 Cov.: 32 AF XY: 0.00987 AC XY: 735 AN XY: 74478

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0153 Hom.: 33

Bravo AF: 0.00986

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0176 AC: 151

ExAC AF: 0.0110 AC: 1337

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0163

EpiControl AF: 0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CARD14: BS1, BS2; ENSG00000262580: BS1, BS2 -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;T;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.30
MPC		0.66
ClinPred		0.043	T
GERP RS		4.9
Varity_R		0.81
gMVP		0.71

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: rs117918077; hg19: chr17-78176044; COSMIC: COSV99061894; COSMIC: COSV99061894;