ENST00000696169.1:n.*482G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2

The ENST00000696169.1(ENSG00000289701):n.*482G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,612,174 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 18 hom. )

Consequence

ENSG00000289701
ENST00000696169.1 non_coding_transcript_exon

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 1.57

Publications

21 publications found

Variant links:

Genes affected

ENSG00000289701 (HGNC:):

ENSG00000289701 links:

CARD9 (HGNC:16391): (caspase recruitment domain family member 9) The protein encoded by this gene is a member of the CARD protein family, which is defined by the presence of a characteristic caspase-associated recruitment domain (CARD). CARD is a protein interaction domain known to participate in activation or suppression of CARD containing members of the caspase family, and thus plays an important regulatory role in cell apoptosis. This protein was identified by its selective association with the CARD domain of BCL10, a postive regulator of apoptosis and NF-kappaB activation, and is thought to function as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-kappaB. Several alternatively spliced transcript variants have been observed, but their full-length nature is not clearly defined. [provided by RefSeq, Jul 2008]

CARD9 Gene-Disease associations (from GenCC):

deep dermatophytosis
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
predisposition to invasive fungal disease due to CARD9 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

CARD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 9-136365140-C-G is Benign according to our data. Variant chr9-136365140-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 535816.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CARD9	NM_052813.5 link	c.1434+1G>C	splice_donor_variant, intron_variant	Intron 11 of 12	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4 link	c.1434+1G>C	splice_donor_variant, intron_variant	Intron 11 of 12		NP_434701.1
LOC124902309	XR_007061863.1 link	n.84+1688C>G	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ENSG00000289701	ENST00000696169.1 link	n.*482G>C	non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000512460.1
ENSG00000289701	ENST00000696169.1 link	n.*482G>C	3_prime_UTR_variant	Exon 11 of 13			ENSP00000512460.1
CARD9	ENST00000371732.10 link	c.1434+1G>C	splice_donor_variant, intron_variant	Intron 11 of 12	1	NM_052813.5	ENSP00000360797.5

Frequencies

GnomAD3 genomes

AF:

0.00372

AC:

567

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00638

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00327

AC:

812

AN:

248172

AF XY:

0.00335

show subpopulations

Gnomad AFR exome

AF:

0.000499

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00722

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000926

Gnomad NFE exome

AF:

0.00537

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00470

AC:

6860

AN:

1459836

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

3334

AN XY:

726310

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.00145

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

173

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86252

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

51658

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00559

AC:

6214

AN:

1111820

Other (OTH)

AF:

0.00346

AC:

209

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

337

674

1010

1347

1684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<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:

0.00372

AC:

567

AN:

152338

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41580

American (AMR)

AF:

0.00124

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00638

AC:

434

AN:

68012

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

158

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:

0.00446

Hom.:

Bravo

AF:

0.00369

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00322

AC:

390

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency

Uncertain:3Benign:2

Sep 11, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD9 NM_052813.4 exon 11 c.1434+1G>C: This variant has been reported in the heterozygous state in at least one individual with pulmonary nontuberculous mycobacterial infection (Szymanski 2015 PMID:26038974). This variant is also present in 0.7% (74/10266) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-139259592-C-G), including two homozygotes in the European population. Additionally, this variant has been reported in the literature to have a potentially protective effect for inflammatory bowel disease and Crohn's disease risk (Rivas 2011 PMID: 21983784, Beaudoin 2013 PMID:24068945). This variant is present in ClinVar (Variation ID:535816). Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. However, there is insufficient evidence to establish loss of function as a mechanism of disease for this gene at this time. In addition, this variant occurs towards the 3' end of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial candidiasis 2 (MIM#212050). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity where age of onset and type of fungal infections can be variable. Penetrance is expected to be complete by the age of 52, however, it is incomplete in younger individuals (PMID: 30136218). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (563 heterozygotes, 2 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) (3 heterozygotes, 0 homozygotes). (SB) 0508 - In silico predictions for abnormal splicing are uninformative. (I) 0705 - No comparable canonical splice site variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. This variant has previously been reported as likely benign (3x) and VUS (1x) in ClinVar. It has also been reported in a patient with primary immunodeficiency where one homozygous variant in each of the MYD88 and CARD9 genes was identified, and the patient's clinical phenotype was thought to be due to MYD88-deficiency (PMID: 30837984). Additionally, this variant was reported in a conference abstract in homozygous state in a child with recurrent fungal infection (PMID: 30809743). In the heterozygous state, this variant has been reported to confer strong effective effects against inflammatory bowel disease (PMID: 33414972). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:3Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD9: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Benign

0.96

Eigen

Uncertain

0.47

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.25

PhyloP100

1.6

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=94/6

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.88

Position offset: 1

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over