7-2930015-T-G

Position:

chr7-2930015-T-G

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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:7O:1

Conservation

PhyloP100: -1.80

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 -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 id is 133785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2930015-T-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD11	NM_032415.7 link	c.1630A>C	p.Ile544Leu	missense_variant	12/25	ENST00000396946.9	NP_115791.3	Q9BXL7A0A024R854Q8TES3
CARD11	NM_001324281.3 link	c.1630A>C	p.Ile544Leu	missense_variant	13/26		NP_001311210.1	Q9BXL7A0A024R854Q8TES3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CARD11	ENST00000396946.9 link	c.1630A>C	p.Ile544Leu	missense_variant	12/25	1	NM_032415.7	ENSP00000380150.4	Q9BXL7
CARD11	ENST00000355508.3 link	c.46A>C	p.Ile16Leu	missense_variant	1/7	3		ENSP00000347695.3	H7BY05
CARD11	ENST00000698637.1 link	n.1956A>C		non_coding_transcript_exon_variant	12/24

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

GnomAD3 exomes

AF:

0.00235

AC:

591

AN:

251262

Hom.:

AF XY:

0.00239

AC XY:

324

AN XY:

135806

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 SAS exome

AF:

0.000621

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

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.00650

Gnomad4 NFE exome

AF:

0.00365

Gnomad4 OTH exome

AF:

0.00275

GnomAD4 genome

AF:

0.00264

AC:

402

AN:

152218

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00791

Gnomad4 NFE

AF:

0.00372

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00280

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:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CARD11: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2019	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) -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 20, 2016	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.0030

DANN

Benign

0.79

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.047

Sift

Benign

0.85

T;D

Sift4G

Benign

0.94

T;.

Polyphen

0.0

B;.

Vest4

0.30

MVP

0.32

MPC

0.45

ClinPred

0.00012

GERP RS

-0.89

Varity_R

0.024

gMVP

0.13

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

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