Genetic Variant CARD11:p.Thr532Arg (chr7-2930050-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032415.7(CARD11):c.1595C>G(p.Thr532Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T532M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.785

Publications

0 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 Gene-Disease associations (from GenCC):

BENTA disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
immunodeficiency 11b with atopic dermatitis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
severe combined immunodeficiency due to CARD11 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet

CARD11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.082794756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD11	NM_032415.7 link	c.1595C>G	p.Thr532Arg	missense_variant	Exon 12 of 25	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3 link	c.1595C>G	p.Thr532Arg	missense_variant	Exon 13 of 26		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CARD11	ENST00000396946.9 link	c.1595C>G	p.Thr532Arg	missense_variant	Exon 12 of 25	1	NM_032415.7	ENSP00000380150.4
CARD11	ENST00000355508.3 link	c.11C>G	p.Thr4Arg	missense_variant	Exon 1 of 7	3		ENSP00000347695.3
CARD11	ENST00000698637.1 link	n.1921C>G		non_coding_transcript_exon_variant	Exon 12 of 24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111820

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.085

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.

PhyloP100

-0.79

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.091

Sift

Benign

0.22

T;D

Sift4G

Benign

0.41

T;.

Vest4

0.12

ClinPred

0.051

GERP RS

-5.2

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.056

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over