9-136371349-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052813.5(CARD9):c.297G>A(p.Pro99=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,602,174 control chromosomes in the GnomAD database, including 838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (82 hom., cov: 34)
  • Exomes 𝑓: 0.020 (756 hom.)
• Consequence: CARD9 NM_052813.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.818

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=-0.85).
• BP6: Variant 9-136371349-C-T is Benign according to our data. Variant chr9-136371349-C-T is described in ClinVar as [Benign]. Clinvar id is 365853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136371349-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.818 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD9	NM_052813.5	c.297G>A	p.Pro99=	synonymous_variant	3/13	ENST00000371732.10
CARD9	NM_052814.4	c.297G>A	p.Pro99=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD9	ENST00000371732.10	c.297G>A	p.Pro99=	synonymous_variant	3/13	1	NM_052813.5	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2921 AN: 152212 Hom.: 78 Cov.: 34

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0869

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0326 AC: 7451 AN: 228396 Hom.: 441 AF XY: 0.0269 AC XY: 3338 AN XY: 124132

Gnomad AFR exome AF: 0.00533

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.00380

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0200 AC: 29002 AN: 1449844 Hom.: 756 Cov.: 34 AF XY: 0.0190 AC XY: 13712 AN XY: 720220

Gnomad4 AFR exome AF: 0.00420

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.000688

Gnomad4 SAS exome AF: 0.00391

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0193 AC: 2933 AN: 152330 Hom.: 82 Cov.: 34 AF XY: 0.0193 AC XY: 1436 AN XY: 74496

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.0876

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0167 Hom.: 15

Bravo AF: 0.0254

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Illumina Laboratory Services, Illumina	Mar 08, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.69
Dann	Benign	0.90

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

Other links and lift over

dbSNP: rs115131813; hg19: chr9-139265801; COSMIC: COSV53739282; COSMIC: COSV53739282;