rs281875214

chr17-80183976-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_001366385.1(CARD14):c.413A>C(p.Glu138Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E138K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.97

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80183975-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 597197.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 17-80183976-A-C is Pathogenic according to our data. Variant chr17-80183976-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 31609.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-80183976-A-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33008808).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.413A>C	p.Glu138Ala	missense_variant	7/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.413A>C	p.Glu138Ala	missense_variant	7/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Psoriasis 2, pustular Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2012

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.99	D;D;.;D
Vest4		0.81
MutPred		0.15		Loss of disorder (P = 0.0724);Loss of disorder (P = 0.0724);Loss of disorder (P = 0.0724);Loss of disorder (P = 0.0724);
MVP		0.88
MPC		0.67
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.27
gMVP		0.74

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: rs281875214; hg19: chr17-78157775;