chr9-136364163-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_052814.4(CARD9):c.1442-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,550,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
CARD9
NM_052814.4 splice_acceptor, intron
NM_052814.4 splice_acceptor, intron
Scores
7
Splicing: ADA: 0.0001350
2
Clinical Significance
Conservation
PhyloP100: -2.74
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 Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1392833 fraction of the gene.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CARD9 | NM_052813.5 | c.*139G>A | 3_prime_UTR_variant | 13/13 | ENST00000371732.10 | NP_434700.2 | ||
| CARD9 | NM_052814.4 | c.1442-1G>A | splice_acceptor_variant, intron_variant | NP_434701.1 | ||||
| LOC124902309 | XR_007061863.1 | n.84+711C>T | intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CARD9 | ENST00000371732 | c.*139G>A | 3_prime_UTR_variant | 13/13 | 1 | NM_052813.5 | ENSP00000360797.5 | |||
| ENSG00000289701 | ENST00000696169.1 | n.*1378G>A | non_coding_transcript_exon_variant | 12/13 | ENSP00000512460.1 | |||||
| ENSG00000289701 | ENST00000696169.1 | n.*1378G>A | 3_prime_UTR_variant | 12/13 | ENSP00000512460.1 |
Frequencies
GnomAD3 genomes 0.000190 AC: 29AN: 152244Hom.: 0 Cov.: 34
GnomAD3 genomes
AF:
AC:
29
AN:
152244
Hom.:
Cov.:
34
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000967 AC: 15AN: 155052Hom.: 0 AF XY: 0.0000728 AC XY: 6AN XY: 82372
GnomAD3 exomes
AF:
AC:
15
AN:
155052
Hom.:
AF XY:
AC XY:
6
AN XY:
82372
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000167 AC: 233AN: 1398184Hom.: 0 Cov.: 32 AF XY: 0.000157 AC XY: 108AN XY: 689622
GnomAD4 exome
AF:
AC:
233
AN:
1398184
Hom.:
Cov.:
32
AF XY:
AC XY:
108
AN XY:
689622
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000190 AC: 29AN: 152362Hom.: 0 Cov.: 34 AF XY: 0.000174 AC XY: 13AN XY: 74506
GnomAD4 genome
AF:
AC:
29
AN:
152362
Hom.:
Cov.:
34
AF XY:
AC XY:
13
AN XY:
74506
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
4
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Predisposition to invasive fungal disease due to CARD9 deficiency Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at