rs115057256

chr9-136370375-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_052813.5(CARD9):c.870G>A(p.Ala290=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,609,816 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: CARD9 NM_052813.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.75

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-136370375-C-T is Benign according to our data. Variant chr9-136370375-C-T is described in ClinVar as [Benign]. Clinvar id is 365843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1744/152352) while in subpopulation AFR AF= 0.0396 (1645/41584). AF 95% confidence interval is 0.038. There are 37 homozygotes in gnomad4. There are 845 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD9	NM_052813.5	c.870G>A	p.Ala290=	synonymous_variant	6/13	ENST00000371732.10
CARD9	NM_052814.4	c.870G>A	p.Ala290=	synonymous_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD9	ENST00000371732.10	c.870G>A	p.Ala290=	synonymous_variant	6/13	1	NM_052813.5	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1744 AN: 152234 Hom.: 37 Cov.: 34

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00281 AC: 679 AN: 241562 Hom.: 14 AF XY: 0.00204 AC XY: 269 AN XY: 131560

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00118 AC: 1723 AN: 1457464 Hom.: 29 Cov.: 33 AF XY: 0.00107 AC XY: 774 AN XY: 724882

Gnomad4 AFR exome AF: 0.0413

Gnomad4 AMR exome AF: 0.00225

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000700

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000729

Gnomad4 OTH exome AF: 0.00226

GnomAD4 genome AF: 0.0114 AC: 1744 AN: 152352 Hom.: 37 Cov.: 34 AF XY: 0.0113 AC XY: 845 AN XY: 74494

Gnomad4 AFR AF: 0.0396

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00565 Hom.: 6

Bravo AF: 0.0125

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.1
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs115057256; hg19: chr9-139264827;