chr7-2906649-C-T

Position:

chr7-2906649-C-T

Variant summary

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

The NM_032415.7(CARD11):c.3454G>A(p.Asp1152Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000419 in 1,613,378 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 7.20

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:

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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=0.0068109334).

BP6

Variant 7-2906649-C-T is Benign according to our data. Variant chr7-2906649-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00201 (306/152388) while in subpopulation AFR AF= 0.00683 (284/41594). AF 95% confidence interval is 0.00618. There are 2 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7 linkuse as main transcript	c.3454G>A	p.Asp1152Asn	missense_variant	25/25	ENST00000396946.9
CARD11	NM_001324281.3 linkuse as main transcript	c.3454G>A	p.Asp1152Asn	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CARD11	ENST00000396946.9 linkuse as main transcript	c.3454G>A	p.Asp1152Asn	missense_variant	25/25	1	NM_032415.7	P1
CARD11	ENST00000698637.1 linkuse as main transcript	n.4564G>A		non_coding_transcript_exon_variant	24/24
CARD11	ENST00000698652.1 linkuse as main transcript	n.2410G>A		non_coding_transcript_exon_variant	8/8

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

306

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00685

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000579

AC:

145

AN:

250454

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.00751

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1460990

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

726686

show subpopulations

Gnomad4 AFR exome

AF:

0.00774

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000746

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

152388

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00683

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000494

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other: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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Severe combined immunodeficiency due to CARD11 deficiency;C4539957:Immunodeficiency 11b with atopic dermatitis;C4551967:BENTA disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 18, 2022

- -

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

0.094

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.035

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Benign

0.19

Sift4G

Benign

0.13

Polyphen

0.86

Vest4

0.32

MVP

0.49

MPC

0.61

ClinPred

0.037

GERP RS

3.8

Varity_R

0.16

gMVP

0.43

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