chr7-2930015-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032415.7(CARD11):c.1630A>C(p.Ile544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,613,798 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 13 hom. )

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -1.80

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036149025).

BP6

Variant 7-2930015-T-G is Benign according to our data. Variant chr7-2930015-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 133785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00264 (402/152218) while in subpopulation NFE AF = 0.00372 (253/67982). AF 95% confidence interval is 0.00334. There are 3 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032415.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	NM_032415.7	MANE Select	c.1630A>C	p.Ile544Leu	missense	Exon 12 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.1630A>C	p.Ile544Leu	missense	Exon 13 of 26	NP_001311210.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CARD11	ENST00000396946.9	TSL:1 MANE Select	c.1630A>C	p.Ile544Leu	missense	Exon 12 of 25	ENSP00000380150.4
CARD11	ENST00000355508.3	TSL:3	c.46A>C	p.Ile16Leu	missense	Exon 1 of 7	ENSP00000347695.3
CARD11	ENST00000698637.1		n.1956A>C		non_coding_transcript_exon	Exon 12 of 24

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00791

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00374

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00235

AC:

591

AN:

251262

AF XY:

0.00239

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00671

Gnomad NFE exome

AF:

0.00312

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00325

AC:

4750

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2324

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33476

American (AMR)

AF:

0.00159

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000765

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00650

AC:

347

AN:

53378

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00365

AC:

4062

AN:

1111816

Other (OTH)

AF:

0.00275

AC:

166

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

222

444

666

888

1110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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

AF:

0.00264

AC:

402

AN:

152218

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41532

American (AMR)

AF:

0.00163

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00125

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00791

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00372

AC:

253

AN:

67982

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00196

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00217

AC:

263

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD11: BP4, BS2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 24, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33206719, 30170123)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Oct 20, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.0030

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.16

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.62

M_CAP

Benign

0.013

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-1.8

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.16

REVEL

Benign

0.047

Sift

Benign

0.85

Sift4G

Benign

0.94

Polyphen

0.0

Vest4

0.30

MVP

0.32

MPC

0.45

ClinPred

0.00012

GERP RS

-0.89

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.024

gMVP

0.13

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over