chr9-136371953-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_052813.5(CARD9):c.126C>T(p.Pro42Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,609,980 control chromosomes in the GnomAD database, including 140,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11482 hom., cov: 34)

Exomes 𝑓: 0.42 ( 129058 hom. )

Consequence

CARD9
NM_052813.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.07

Publications

138 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 9-136371953-G-A is Benign according to our data. Variant chr9-136371953-G-A is described in ClinVar as Benign. ClinVar VariationId is 365857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5 link	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 2 of 13	ENST00000371732.10	NP_434700.2	Q9H257-1A0A024R8F1
CARD9	NM_052814.4 link	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 2 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.126C>T	p.Pro42Pro	synonymous_variant	Exon 2 of 13	1	NM_052813.5	ENSP00000360797.5		Q9H257-1
ENSG00000289701	ENST00000696169.1 link	n.126C>T		non_coding_transcript_exon_variant	Exon 2 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57880

AN:

152020

Hom.:

11464

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.357

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.423

Gnomad OTH

AF:

0.357

GnomAD2 exomes

AF:

0.407

AC:

102015

AN:

250490

AF XY:

0.399

show subpopulations

Gnomad AFR exome

AF:

0.283

Gnomad AMR exome

AF:

0.537

Gnomad ASJ exome

AF:

0.358

Gnomad EAS exome

AF:

0.297

Gnomad FIN exome

AF:

0.418

Gnomad NFE exome

AF:

0.427

Gnomad OTH exome

AF:

0.411

GnomAD4 exome

AF:

0.417

AC:

607724

AN:

1457842

Hom.:

129058

Cov.:

AF XY:

0.413

AC XY:

299109

AN XY:

724554

show subpopulations

African (AFR)

AF:

0.278

AC:

9292

AN:

33432

American (AMR)

AF:

0.535

AC:

23905

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

9259

AN:

26108

East Asian (EAS)

AF:

0.318

AC:

12591

AN:

39586

South Asian (SAS)

AF:

0.320

AC:

27612

AN:

86214

European-Finnish (FIN)

AF:

0.417

AC:

21786

AN:

52200

Middle Eastern (MID)

AF:

0.241

AC:

1385

AN:

5758

European-Non Finnish (NFE)

AF:

0.431

AC:

478021

AN:

1109672

Other (OTH)

AF:

0.396

AC:

23873

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

24348

48697

73045

97394

121742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14520

29040

43560

58080

72600

<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:

0.381

AC:

57944

AN:

152138

Hom.:

11482

Cov.:

AF XY:

0.379

AC XY:

28175

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.288

AC:

11946

AN:

41486

American (AMR)

AF:

0.475

AC:

7263

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

1237

AN:

3464

East Asian (EAS)

AF:

0.309

AC:

1600

AN:

5170

South Asian (SAS)

AF:

0.329

AC:

1588

AN:

4830

European-Finnish (FIN)

AF:

0.411

AC:

4355

AN:

10596

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.423

AC:

28756

AN:

67986

Other (OTH)

AF:

0.359

AC:

758

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1882

3764

5645

7527

9409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

550

1100

1650

2200

2750

<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:

0.405

Hom.:

48966

Bravo

AF:

0.379

Asia WGS

AF:

0.385

AC:

1338

AN:

3478

EpiCase

AF:

0.393

EpiControl

AF:

0.408

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 76% of patients studied by a panel of primary immunodeficiencies. Number of patients: 67. Only high quality variants are reported. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.2

(source)

DANN

Benign

0.91

PhyloP100

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over