rs571517554

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_Moderate

The NM_032415.7(CARD11):c.368G>A(p.Gly123Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,030 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G123S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.55

Publications

21 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: Likely_pathogenic. The variant received 9 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 chr7-2944529-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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

PP5

Variant 7-2944528-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD11	NM_032415.7 link	c.368G>A	p.Gly123Asp	missense_variant	Exon 5 of 25	ENST00000396946.9	NP_115791.3	Q9BXL7A0A024R854Q8TES3
CARD11	NM_001324281.3 link	c.368G>A	p.Gly123Asp	missense_variant	Exon 6 of 26		NP_001311210.1	Q9BXL7A0A024R854Q8TES3
CARD11-AS1	NR_187443.1 link	n.474+20C>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.368G>A	p.Gly123Asp	missense_variant	Exon 5 of 25	1	NM_032415.7	ENSP00000380150.4		Q9BXL7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247716

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459684

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725896

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110808

Other (OTH)

AF:

0.00

AC:

AN:

60316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74500

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 123 of the CARD11 protein (p.Gly123Asp). This variant is present in population databases (rs571517554, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant B-cell expansion with NFKB and T-cell anergy (BENTA) (PMID: 25352053). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183144). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CARD11 function (PMID: 23149938, 25352053). This variant disrupts the p.Gly123 amino acid residue in CARD11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23129749, 26861442, 29472930). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

BENTA disease

Pathogenic:1

Oct 29, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.8

PhyloP100

5.5

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.22

Sift

Benign

0.21

Sift4G

Pathogenic

0.0

Polyphen

0.93

Vest4

0.94

MutPred

0.29

Gain of disorder (P = 0.2072);

MVP

0.68

MPC

3.5

ClinPred

0.97

GERP RS

4.2

Varity_R

0.68

gMVP

0.97

Mutation Taster

=18/82

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

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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