rs141992399

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_052813.5(CARD9):c.1434+1G>C variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. 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

CARD9
NM_052813.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 1.57

Variant links:

Genes affected

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 links:

ENSG00000289701 (HGNC:):

ENSG00000289701 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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 id is 535816.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00372 (567/152338) while in subpopulation NFE AF= 0.00638 (434/68012). AF 95% confidence interval is 0.00589. There are 2 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CARD9	NM_052813.5 linkuse as main transcript	c.1434+1G>C	splice_donor_variant, intron_variant	ENST00000371732.10	NP_434700.2	Q9H257-1A0A024R8F1
CARD9	NM_052814.4 linkuse as main transcript	c.1434+1G>C	splice_donor_variant, intron_variant		NP_434701.1	Q9H257-2
LOC124902309	XR_007061863.1 linkuse as main transcript	n.84+1688C>G	intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CARD9	ENST00000371732.10 linkuse as main transcript	c.1434+1G>C	splice_donor_variant, intron_variant		1	NM_052813.5	ENSP00000360797.5	Q9H257-1
ENSG00000289701	ENST00000696169.1 linkuse as main transcript	n.*482G>C	non_coding_transcript_exon_variant	11/13			ENSP00000512460.1
ENSG00000289701	ENST00000696169.1 linkuse as main transcript	n.*482G>C	3_prime_UTR_variant	11/13			ENSP00000512460.1

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

GnomAD3 exomes

AF:

0.00327

AC:

812

AN:

248172

Hom.:

AF XY:

0.00335

AC XY:

451

AN XY:

134752

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 SAS exome

AF:

0.00163

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

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.00662

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00114

Gnomad4 NFE exome

AF:

0.00559

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.00372

AC:

567

AN:

152338

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00638

Gnomad4 OTH

AF:

0.000946

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:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CARD9: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Predisposition to invasive fungal disease due to CARD9 deficiency

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Benign

0.96

Eigen

Uncertain

0.47

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.25

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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