rs145474800

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000396946.9(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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARD11 ENST00000396946.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 19 ACMG points.

• PM1: In a domain CARD (size 92) in uniprot entity CAR11_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000396946.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-2947707-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184594.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CARD11. . Gene score misZ 3.5439 (greater than the threshold 3.09). Trascript score misZ 3.7177 (greater than threshold 3.09). GenCC has associacion of gene with BENTA disease, immunodeficiency 11b with atopic dermatitis, severe combined immunodeficiency due to CARD11 deficiency.
• 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 [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/exons	MANE	Protein	UniProt
CARD11	NM_032415.7	c.88C>T	p.Arg30Trp	missense_variant	3/25	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3	c.88C>T	p.Arg30Trp	missense_variant	4/26		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9	c.88C>T	p.Arg30Trp	missense_variant	3/25	1	NM_032415.7	ENSP00000380150	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CARD11 function (PMID: 28826773). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 473938). This missense change has been observed in individual(s) with clinical features of atopy and combined immunodeficiency (PMID: 28826773; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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). -

Immunodeficiency 11b with atopic dermatitis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

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

-

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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 07, 2018

- -

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;.
MutationTaster	Benign	1.0	D
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;