chr17-80181478-C-G

Position:

• chr17-80181478-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366385.1(CARD14):​c.40C>G​(p.Leu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13159159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.40C>G	p.Leu14Val	missense_variant	5/24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.40C>G	p.Leu14Val	missense_variant	5/24		NM_001366385.1	ENSP00000498071	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436292 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 20, 2018

This sequence change replaces leucine with valine at codon 14 of the CARD14 protein (p.Leu14Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CARD14-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T;T;.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.61	.;.;.;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;M;.;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	.;.;.;.;.;N
REVEL	Benign	0.022
Sift	Benign	0.048	.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;T;.;T;T;T
Polyphen		0.11	.;B;B;.;.;B
Vest4		0.18, 0.20
MutPred		0.25		Loss of stability (P = 0.077);Loss of stability (P = 0.077);Loss of stability (P = 0.077);Loss of stability (P = 0.077);Loss of stability (P = 0.077);Loss of stability (P = 0.077);
MVP		0.82
MPC		0.55
ClinPred		0.38	T
GERP RS		0.99
Varity_R		0.088
gMVP		0.40

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: rs1598634057; hg19: chr17-78155277;