rs387907352

Positions:

• chr7-2944529-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.47

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

ACMG classification

Verdict is Pathogenic. Variant got 17 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 chr7-2944528-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 183144.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, CARD11
• 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 id is 48648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2944529-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7	c.367G>A	p.Gly123Ser	missense_variant	5/25	ENST00000396946.9
CARD11	NM_001324281.3	c.367G>A	p.Gly123Ser	missense_variant	6/26
CARD11-AS1	XR_926993.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9	c.367G>A	p.Gly123Ser	missense_variant	5/25	1	NM_032415.7	P1
CARD11-AS1	ENST00000423194.1	n.474+21C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459628 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

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 Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BENTA disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 19, 2012	- -
Pathogenic, no assertion criteria provided	literature only	Molecular Diagnosis for Inborn Errors of Immunity, Hospital de Pediatria Garrahan	-	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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

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. 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). This variant is not present in population databases (gnomAD no frequency). 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 also known as G116S. ClinVar contains an entry for this variant (Variation ID: 48648). 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. Experimental studies have shown that this missense change affects CARD11 function (PMID: 23027925, 23129749, 25352053). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

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

Asthma;C0029453:Osteopenia;C0038002:Splenomegaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 06, 2021

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	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.25
Sift	Benign	0.054	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.26		Gain of phosphorylation at G123 (P = 0.0884);
MVP		0.82
MPC		3.1
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.53
gMVP		0.95

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: rs387907352; hg19: chr7-2984163; COSMIC: COSV62717009; COSMIC: COSV62717009;