rs59902911

Positions:

• chr9-136370636-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.693G>A​(p.Thr231Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,612,742 control chromosomes in the GnomAD database, including 1,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (141 hom., cov: 34)
  • Exomes 𝑓: 0.034 (991 hom.)
• Consequence: CARD9 NM_052813.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 9-136370636-C-T is Benign according to our data. Variant chr9-136370636-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 365848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136370636-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD9	NM_052813.5	c.693G>A	p.Thr231Thr	synonymous_variant	5/13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.693G>A	p.Thr231Thr	synonymous_variant	5/13		NP_434701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.693G>A	p.Thr231Thr	synonymous_variant	5/13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.693G>A		non_coding_transcript_exon_variant	5/13			ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 6055 AN: 152232 Hom.: 140 Cov.: 34

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.0973

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0386 AC: 9617 AN: 249382 Hom.: 243 AF XY: 0.0383 AC XY: 5183 AN XY: 135366

Gnomad AFR exome AF: 0.0523

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.0410

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0336 AC: 49133 AN: 1460392 Hom.: 991 Cov.: 33 AF XY: 0.0339 AC XY: 24600 AN XY: 726488

Gnomad4 AFR exome AF: 0.0492

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.0832

Gnomad4 SAS exome AF: 0.0399

Gnomad4 FIN exome AF: 0.0455

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0367

GnomAD4 genome AF: 0.0398 AC: 6065 AN: 152350 Hom.: 141 Cov.: 34 AF XY: 0.0400 AC XY: 2980 AN XY: 74500

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.0969

Gnomad4 SAS AF: 0.0526

Gnomad4 FIN AF: 0.0454

Gnomad4 NFE AF: 0.0336

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0368 Hom.: 53

Bravo AF: 0.0370

Asia WGS AF: 0.0950 AC: 331 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0290

ClinVar

Significance: Benign/Likely 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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.85
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs59902911; hg19: chr9-139265088; COSMIC: COSV53733487; COSMIC: COSV53733487;