rs387907352

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_032415.7(CARD11):c.367G>A(p.Gly123Ser) variant causes a missense change. 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. G123D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.47

Publications

25 publications found

Variant links:

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]

CARD11 links:

CARD11-AS1 (HGNC:40766): (CARD11 antisense RNA 1)

CARD11-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_032415.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-2944528-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 183144.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant 7-2944529-C-T is Pathogenic according to our data. Variant chr7-2944529-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 48648.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 link	c.367G>A	p.Gly123Ser	missense_variant	Exon 5 of 25	ENST00000396946.9	NP_115791.3	Q9BXL7A0A024R854Q8TES3
CARD11	NM_001324281.3 link	c.367G>A	p.Gly123Ser	missense_variant	Exon 6 of 26		NP_001311210.1	Q9BXL7A0A024R854Q8TES3
CARD11-AS1	NR_187443.1 link	n.474+21C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9 link	c.367G>A	p.Gly123Ser	missense_variant	Exon 5 of 25	1	NM_032415.7	ENSP00000380150.4		Q9BXL7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725874

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110810

Other (OTH)

AF:

0.00

AC:

AN:

60320

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BENTA disease

Pathogenic:2

Nov 19, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

The Gly123Ser variant in CARD11 has been reported in BENTA patients (Meitlis et al 2020 Am J Hum Genetics, Ma CA et al 2017 Nature Genetics, Snow AL et al 2012 J Exp Med) and was absent from large population studies. Additionally, in vitro functional studies indicate that the Gly123Ser variant significantly increased NF-kB reporter signal, either with or without stimulation by anti-CD3/CD28 antibodies (Meitlis et al 2020 Am J Hum Genetics, Ma CA et al 2017 Nature Genetics). -

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

Pathogenic:1

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly123 amino acid residue in CARD11. Other variant(s) that disrupt this residue have been observed in individuals with CARD11-related conditions (PMID: 25352053, 28824638), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects CARD11 function (PMID: 23027925, 23129749, 25352053). 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 expected to disrupt CARD11 protein function. ClinVar contains an entry for this variant (Variation ID: 48648). This variant is also known as G116S. This missense change has been observed in individual(s) with autosomal dominant B-cell expansion with NFKB and T-cell anergy (BENTA) (PMID: 23129749, 26861442, 29472930). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 123 of the CARD11 protein (p.Gly123Ser). -

not provided

Pathogenic:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD11: PM1, PM2, PP4:Moderate, PS3:Moderate, PS4:Moderate, PP2 -

Asthma;C0029453:Osteopenia;C0038002:Splenomegaly

Pathogenic:1

Dec 06, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 strong, PM2 moderate, PM5, PM6 moderate, PP2 supporting, BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.2

PhyloP100

5.5

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.9

REVEL

Benign

0.25

Sift

Benign

0.054

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.26

Gain of phosphorylation at G123 (P = 0.0884);

MVP

0.82

MPC

3.1

ClinPred

0.99

GERP RS

4.2

Varity_R

0.53

gMVP

0.95

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over