9-136364342-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052813.5(CARD9):ā€‹c.1571A>Cā€‹(p.Asn524Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,568,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00034 ( 0 hom., cov: 34)
Exomes š‘“: 0.00064 ( 1 hom. )

Consequence

CARD9
NM_052813.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.95
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17912549).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CARD9NM_052813.5 linkc.1571A>C p.Asn524Thr missense_variant Exon 13 of 13 ENST00000371732.10 NP_434700.2 Q9H257-1A0A024R8F1
CARD9NM_052814.4 linkc.1442-180A>C intron_variant Intron 12 of 12 NP_434701.1 Q9H257-2
LOC124902309XR_007061863.1 linkn.84+890T>G intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CARD9ENST00000371732.10 linkc.1571A>C p.Asn524Thr missense_variant Exon 13 of 13 1 NM_052813.5 ENSP00000360797.5 Q9H257-1
ENSG00000289701ENST00000696169.1 linkn.*1199A>C non_coding_transcript_exon_variant Exon 12 of 13 ENSP00000512460.1
ENSG00000289701ENST00000696169.1 linkn.*1199A>C 3_prime_UTR_variant Exon 12 of 13 ENSP00000512460.1

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
152162
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
38
AN:
180228
Hom.:
0
AF XY:
0.000186
AC XY:
18
AN XY:
96622
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000408
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000478
Gnomad OTH exome
AF:
0.000206
GnomAD4 exome
AF:
0.000637
AC:
902
AN:
1416156
Hom.:
1
Cov.:
32
AF XY:
0.000590
AC XY:
413
AN XY:
700544
show subpopulations
Gnomad4 AFR exome
AF:
0.0000308
Gnomad4 AMR exome
AF:
0.0000261
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000766
Gnomad4 OTH exome
AF:
0.00111
GnomAD4 genome
AF:
0.000342
AC:
52
AN:
152162
Hom.:
0
Cov.:
34
AF XY:
0.000242
AC XY:
18
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000506
Hom.:
0
Bravo
AF:
0.000359
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000229
AC:
1
ESP6500EA
AF:
0.000704
AC:
6
ExAC
AF:
0.000118
AC:
14

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency Uncertain:2
Feb 21, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 524 of the CARD9 protein (p.Asn524Thr). This variant is present in population databases (rs141310444, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CARD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 535814). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1
Jul 13, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1571A>C (p.N524T) alteration is located in exon 13 (coding exon 12) of the CARD9 gene. This alteration results from a A to C substitution at nucleotide position 1571, causing the asparagine (N) at amino acid position 524 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
19
DANN
Benign
0.88
DEOGEN2
Benign
0.28
T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.58
T
M_CAP
Pathogenic
0.42
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.17
Sift
Uncertain
0.029
D
Sift4G
Uncertain
0.057
T
Polyphen
0.90
P
Vest4
0.25
MVP
0.46
MPC
0.23
ClinPred
0.081
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.076
gMVP
0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141310444; hg19: chr9-139258794; COSMIC: COSV99056932; COSMIC: COSV99056932; API