17-80198529-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.928

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 458090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80198529-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1575 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.1789C>T	p.Arg597Trp	missense_variant	16/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.1789C>T	p.Arg597Trp	missense_variant	16/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1575 AN: 152258 Hom.: 19 Cov.: 32

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

GnomAD3 exomes AF: 0.00287 AC: 716 AN: 249616 Hom.: 13 AF XY: 0.00220 AC XY: 297 AN XY: 135254

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 SAS exome AF: 0.0000654

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.: 31 Cov.: 32 AF XY: 0.000901 AC XY: 655 AN XY: 726776

Gnomad4 AFR exome AF: 0.0366

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.0103 AC: 1576 AN: 152376 Hom.: 19 Cov.: 32 AF XY: 0.0103 AC XY: 764 AN XY: 74514

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00529 Hom.: 10

Bravo AF: 0.0124

ESP6500AA AF: 0.0363 AC: 160

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00340 AC: 413

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

CARD14: BP4, BS1, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.030	T;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.52	D
MetaRNN	Benign	0.0063	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M;M;M;M
MutationTaster	Benign	0.83	D;D;D;N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.0030	D;.;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.58
MVP		0.87
MPC		0.64
ClinPred		0.035	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.43

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: rs73429414; hg19: chr17-78172328;