rs571517554

Positions:

chr7-2944528-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_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

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 made for transcript

Verdict is Pathogenic. Variant got 10 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, 5 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 id is 48648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, CARD11

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 id is 183144.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CARD11	NM_032415.7 linkuse as main transcript	c.368G>A	p.Gly123Asp	missense_variant	5/25	ENST00000396946.9
CARD11	NM_001324281.3 linkuse as main transcript	c.368G>A	p.Gly123Asp	missense_variant	6/26
CARD11-AS1	XR_926993.2 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9 linkuse as main transcript	c.368G>A	p.Gly123Asp	missense_variant	5/25	1	NM_032415.7	P1
CARD11-AS1	ENST00000423194.1 linkuse as main transcript	n.474+20C>T		intron_variant, non_coding_transcript_variant		1

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

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459684

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

BENTA disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 29, 2014

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

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. Experimental studies have shown that this missense change affects CARD11 function (PMID: 23149938, 25352053). 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"). ClinVar contains an entry for this variant (Variation ID: 183144). 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. This variant is present in population databases (rs571517554, gnomAD 0.01%). 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). -

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

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

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over