Genetic Variant CARD9:p.Arg101Cys (chr9-136371345-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_052813.5(CARD9):c.301C>T(p.Arg101Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CARD9
NM_052813.5 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 1.54

Publications

16 publications found

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 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:

ENSG00000289701 (HGNC:):

ENSG00000289701 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5 link	c.301C>T	p.Arg101Cys	missense_variant	Exon 3 of 13	ENST00000371732.10	NP_434700.2	Q9H257-1A0A024R8F1
CARD9	NM_052814.4 link	c.301C>T	p.Arg101Cys	missense_variant	Exon 3 of 13		NP_434701.1	Q9H257-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10 link	c.301C>T	p.Arg101Cys	missense_variant	Exon 3 of 13	1	NM_052813.5	ENSP00000360797.5		Q9H257-1
ENSG00000289701	ENST00000696169.1 link	n.301C>T		non_coding_transcript_exon_variant	Exon 3 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720788

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

43494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25876

East Asian (EAS)

AF:

0.00

AC:

AN:

39258

South Asian (SAS)

AF:

0.00

AC:

AN:

84646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107372

Other (OTH)

AF:

0.00

AC:

AN:

59944

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency

Other:1

Oct 31, 2013

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

1.5

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.85

MutPred

0.46

Loss of disorder (P = 0.0464);Loss of disorder (P = 0.0464);

MVP

0.31

MPC

2.0

ClinPred

0.99

GERP RS

2.8

Varity_R

0.79

gMVP

0.42

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over