rs1135314

Positions:

• chr9-136364010-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052813.5(CARD9):​c.*292T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,296,282 control chromosomes in the GnomAD database, including 69,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7620 hom., cov: 35)
  • Exomes 𝑓: 0.32 (61685 hom.)
• Consequence: CARD9 NM_052813.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0790

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]

LOC124902309 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-136364010-A-G is Benign according to our data. Variant chr9-136364010-A-G is described in ClinVar as [Benign]. Clinvar id is 365828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD9	NM_052813.5	c.*292T>C		3_prime_UTR_variant	13/13	ENST00000371732.10	NP_434700.2
LOC124902309	XR_007061863.1	n.84+558A>G		intron_variant, non_coding_transcript_variant
CARD9	NM_052814.4	c.*115T>C		3_prime_UTR_variant	13/13		NP_434701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.*292T>C		3_prime_UTR_variant	13/13	1	NM_052813.5	ENSP00000360797	P1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46890 AN: 152100 Hom.: 7606 Cov.: 35

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.335

GnomAD3 exomes AF: 0.319 AC: 47626 AN: 149294 Hom.: 8577 AF XY: 0.309 AC XY: 24749 AN XY: 80102

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.0436

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.322 AC: 367936 AN: 1144066 Hom.: 61685 Cov.: 16 AF XY: 0.318 AC XY: 183053 AN XY: 575504

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.458

Gnomad4 ASJ exome AF: 0.423

Gnomad4 EAS exome AF: 0.0928

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.308 AC: 46942 AN: 152216 Hom.: 7620 Cov.: 35 AF XY: 0.307 AC XY: 22838 AN XY: 74440

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.0554

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.337

Alfa AF: 0.341 Hom.: 3375

Bravo AF: 0.313

Asia WGS AF: 0.188 AC: 654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 75% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Predisposition to invasive fungal disease due to CARD9 deficiency Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.45

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: rs1135314; hg19: chr9-139258462; COSMIC: COSV52517499; COSMIC: COSV52517499;