rs145474800

Variant names:

• chr7-2947707-G-A
• rs145474800
• NM_032415.7:c.88C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-2947707-G-A
• chr7-2947707-G-C
• chr7-2947707-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_032415.7(CARD11):​c.88C>T​(p.Arg30Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.59

Genes affected

CARD11 (HGNC:16393): (caspase recruitment domain family member 11) The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 7-2947707-G-A is Pathogenic according to our data. Variant chr7-2947707-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 473938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD11	NM_032415.7	c.88C>T	p.Arg30Trp	missense_variant	Exon 3 of 25	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3	c.88C>T	p.Arg30Trp	missense_variant	Exon 4 of 26		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9	c.88C>T	p.Arg30Trp	missense_variant	Exon 3 of 25	1	NM_032415.7	ENSP00000380150.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 30 of the CARD11 protein (p.Arg30Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of atopy and combined immunodeficiency (PMID: 28826773; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 473938). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CARD11 protein function. Experimental studies have shown that this missense change affects CARD11 function (PMID: 28826773). For these reasons, this variant has been classified as Pathogenic. -

Immunodeficiency 11b with atopic dermatitis Pathogenic:1

-

Molecular Diagnosis for Inborn Errors of Immunity, Hospital de Pediatria Garrahan

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

The Arg30Trp variant in CARD11 has been reported in CADINS patients (Dadi H et al 2018 J Allergy Clin Immunol, Dorjbal B et al 2019 J Allergy Clin Immunol), and was absent from large population studies. Additionally, in vitro functional studies indicate that the Arg30Trp variant disrupts NFkB activation induced by wild type CARD11 in a dominant negative manner (Dadi H et al 2018 J Allergy Clin Immunol). -

Severe combined immunodeficiency due to CARD11 deficiency;C4539957:Immunodeficiency 11b with atopic dermatitis;C4551967:BENTA disease Pathogenic:1

May 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 07, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.88		Loss of disorder (P = 0.1271);Loss of disorder (P = 0.1271);
MVP		0.86
MPC		3.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.97

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: rs145474800; hg19: chr7-2987341; COSMIC: COSV62716840; COSMIC: COSV62716840;