9-136367753-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_052813.5(CARD9):c.1153G>C(p.Val385Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,605,422 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 34)

Exomes 𝑓: 0.021 ( 390 hom. )

Consequence

CARD9
NM_052813.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.106

Publications

12 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 9-136367753-C-G is Benign according to our data. Variant chr9-136367753-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 365838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2031/152346) while in subpopulation NFE AF = 0.0231 (1573/68030). AF 95% confidence interval is 0.0222. There are 20 homozygotes in GnomAd4. There are 930 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5 link	c.1153G>C	p.Val385Leu	missense_variant	Exon 8 of 13	ENST00000371732.10	NP_434700.2	Q9H257-1A0A024R8F1
CARD9	NM_052814.4 link	c.1153G>C	p.Val385Leu	missense_variant	Exon 8 of 13		NP_434701.1	Q9H257-2
LOC124902309	XR_007061863.1 link	n.214C>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CARD9	ENST00000371732.10 link	c.1153G>C	p.Val385Leu	missense_variant	Exon 8 of 13	1	NM_052813.5	ENSP00000360797.5	Q9H257-1
ENSG00000289701	ENST00000696169.1 link	n.*200G>C		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000512460.1
ENSG00000289701	ENST00000696169.1 link	n.*200G>C		3_prime_UTR_variant	Exon 8 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2031

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0145

AC:

3453

AN:

237458

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.00447

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0209

AC:

30329

AN:

1453076

Hom.:

390

Cov.:

AF XY:

0.0208

AC XY:

15027

AN XY:

723250

show subpopulations

African (AFR)

AF:

0.00356

AC:

119

AN:

33460

American (AMR)

AF:

0.00408

AC:

182

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00341

AC:

AN:

26082

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.0121

AC:

1042

AN:

86130

European-Finnish (FIN)

AF:

0.0123

AC:

561

AN:

45498

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0246

AC:

27305

AN:

1111528

Other (OTH)

AF:

0.0165

AC:

997

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1911

3822

5734

7645

9556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0133

AC:

2031

AN:

152346

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

930

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00320

AC:

133

AN:

41584

American (AMR)

AF:

0.00627

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00704

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0128

AC:

136

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0231

AC:

1573

AN:

68030

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00479

AC:

ESP6500EA

AF:

0.0216

AC:

185

ExAC

AF:

0.0157

AC:

1891

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0218

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CARD9: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Predisposition to invasive fungal disease due to CARD9 deficiency

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

CARD9-related disorder

Benign:1

Sep 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.21

.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L

PhyloP100

-0.11

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.083

Sift

Benign

0.058

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0020

B;B

Vest4

0.69

MutPred

0.15

Loss of MoRF binding (P = 0.0901);Loss of MoRF binding (P = 0.0901);

MPC

0.078

ClinPred

0.0012

GERP RS

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.072

gMVP

0.13

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-136367753-C-G

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