rs376122142

Positions:

chr7-2922661-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_032415.7(CARD11):c.2242A>G(p.Thr748Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0007 in 1,613,740 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T748M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00073 ( 25 hom. )

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 4.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.009792954).

BP6

Variant 7-2922661-T-C is Benign according to our data. Variant chr7-2922661-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 133796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000394 (60/152294) while in subpopulation SAS AF= 0.0124 (60/4828). AF 95% confidence interval is 0.00991. There are 1 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7 linkuse as main transcript	c.2242A>G	p.Thr748Ala	missense_variant	17/25	ENST00000396946.9
CARD11	NM_001324281.3 linkuse as main transcript	c.2242A>G	p.Thr748Ala	missense_variant	18/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9 linkuse as main transcript	c.2242A>G	p.Thr748Ala	missense_variant	17/25	1	NM_032415.7	P1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00155

AC:

389

AN:

250924

Hom.:

AF XY:

0.00195

AC XY:

265

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0126

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000732

AC:

1070

AN:

1461446

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

752

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.000394

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000818

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.00169

AC:

205

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

CARD11-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

CARD11: BP4, BS1, BS2 -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0098

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

0.92

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.11

Sift

Benign

0.50

T;T

Sift4G

Benign

0.87

T;.

Polyphen

0.027

B;.

Vest4

0.50

MutPred

0.47

Gain of sheet (P = 0.0827);.;

MVP

0.65

MPC

0.48

ClinPred

0.065

GERP RS

5.1

Varity_R

0.074

gMVP

0.47

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