rs114895119

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_052813.5(CARD9):c.809A>T(p.Glu270Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,610,598 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0040 ( 25 hom. )

Consequence

CARD9
NM_052813.5 missense, splice_region

Scores

Splicing: ADA: 0.000004033

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.14

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040002167).

BP6

Variant 9-136370436-T-A is Benign according to our data. Variant chr9-136370436-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr9-136370436-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0037 (564/152270) while in subpopulation AMR AF= 0.00712 (109/15300). AF 95% confidence interval is 0.00604. There are 3 homozygotes in gnomad4. There are 288 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5 link	c.809A>T	p.Glu270Val	missense_variant, splice_region_variant	Exon 6 of 13	ENST00000371732.10	NP_434700.2	Q9H257-1A0A024R8F1
CARD9	NM_052814.4 link	c.809A>T	p.Glu270Val	missense_variant, splice_region_variant	Exon 6 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.809A>T	p.Glu270Val	missense_variant, splice_region_variant	Exon 6 of 13	1	NM_052813.5	ENSP00000360797.5		Q9H257-1
ENSG00000289701	ENST00000696169.1 link	n.809A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00354

AC:

862

AN:

243526

Hom.:

AF XY:

0.00391

AC XY:

518

AN XY:

132534

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00316

Gnomad ASJ exome

AF:

0.000911

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00409

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.00489

Gnomad OTH exome

AF:

0.00608

GnomAD4 exome

AF:

0.00400

AC:

5838

AN:

1458328

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

2940

AN XY:

725362

show subpopulations

Gnomad4 AFR exome

AF:

0.000838

Gnomad4 AMR exome

AF:

0.00339

Gnomad4 ASJ exome

AF:

0.000422

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00466

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.00433

Gnomad4 OTH exome

AF:

0.00405

GnomAD4 genome

AF:

0.00370

AC:

564

AN:

152270

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00712

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00497

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00439

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00431

AC:

ExAC

AF:

0.00350

AC:

423

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency

Uncertain:1Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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 6 p.Glu270Val (c.809A>T): This variant has not been reported in the literature but is present in 0.4% (601/123300) of European alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs114895119). This variant is present in ClinVar (Variation ID:365844). This variant amino acid Valine (Val) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Splice prediction tools suggest that this variant may affect splicing. However, 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. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

CARD9-related disorder

Benign:1

Jul 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CARD9: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.079

.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.040

Sift

Benign

0.27

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0040

B;B

Vest4

0.28

MVP

0.16

MPC

0.092

ClinPred

0.0013

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000040

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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