rs587778152

Positions:

• chr7-2919487-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The ENST00000396946.9(CARD11):​c.2395G>A​(p.Asp799Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D799E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CARD11 ENST00000396946.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: 7.72

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD11	NM_032415.7	c.2395G>A	p.Asp799Asn	missense_variant	18/25	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3	c.2395G>A	p.Asp799Asn	missense_variant	19/26		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9	c.2395G>A	p.Asp799Asn	missense_variant	18/25	1	NM_032415.7	ENSP00000380150	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251358 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 0.00000547 AC: 8 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2022	DNA sequence analysis of the CARD11 gene demonstrated a sequence change, c.2395G>A, in exon 18 that results in an amino acid change, p.Asp799Asn. This sequence change does not appear to have been previously described in individuals with CARD11-related disorders. This sequence change has been described in the gnomAD database in one individual in the East Asian subpopulation which corresponds to a population frequency of 0.0005% (dbSNP rs587778152). The p.Asp799Asn change affects a moderately conserved amino acid residue located in a domain of the CARD11 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp799Asn substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp799Asn change remains unknown at this time. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 799 of the CARD11 protein (p.Asp799Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CARD11-related conditions. ClinVar contains an entry for this variant (Variation ID: 133798). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CARD11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0060	D;.
Polyphen		0.99	D;.
Vest4		0.58
MutPred		0.76		Loss of ubiquitination at K796 (P = 0.1041);.;
MVP		0.48
MPC		0.58
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.58

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: rs587778152; hg19: chr7-2959121; COSMIC: COSV62755850;