17-80181473-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001366385.1(CARD14):c.35C>T(p.Thr12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,586,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T12T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0490

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007400781).
• BP6: Variant 17-80181473-C-T is Benign according to our data. Variant chr17-80181473-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 662047.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr17-80181473-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.35C>T	p.Thr12Met	missense_variant	5/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.35C>T	p.Thr12Met	missense_variant	5/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000181 AC: 37 AN: 204972 Hom.: 0 AF XY: 0.000217 AC XY: 24 AN XY: 110506

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.000329

Gnomad EAS exome AF: 0.0000639

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000796

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000192

GnomAD4 exome AF: 0.000108 AC: 155 AN: 1433950 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 81 AN XY: 710728

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000122

Gnomad4 ASJ exome AF: 0.000235

Gnomad4 EAS exome AF: 0.0000523

Gnomad4 SAS exome AF: 0.0000365

Gnomad4 FIN exome AF: 0.000607

Gnomad4 NFE exome AF: 0.0000938

Gnomad4 OTH exome AF: 0.0000674

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74502

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000996 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 12 of the CARD14 protein (p.Thr12Met). This variant is present in population databases (rs569889639, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CARD14-related conditions. ClinVar contains an entry for this variant (Variation ID: 662047). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CARD14 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.4
Dann	Benign	0.85
DEOGEN2	Benign	0.081	T;T;T;.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.043	N
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0074	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.57	T
Sift4G	Benign	0.068	T;T;.;T;T;T
Polyphen		0.32	.;B;B;.;.;B
Vest4		0.091, 0.090
MVP		0.84
MPC		0.17
ClinPred		0.020	T
GERP RS		3.2
Varity_R		0.031
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs569889639; hg19: chr17-78155272; COSMIC: COSV60127195; COSMIC: COSV60127195;