9-136372044-C-T

Position:

• chr9-136372044-C-T

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.35G>A​(p.Ser12Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,612,496 control chromosomes in the GnomAD database, including 140,040 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11416 hom., cov: 34)
  • Exomes 𝑓: 0.42 (128624 hom.)
• Consequence: CARD9 NM_052813.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.135

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8848918E-5).
• BP6: Variant 9-136372044-C-T is Benign according to our data. Variant chr9-136372044-C-T is described in ClinVar as [Benign]. Clinvar id is 365858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136372044-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD9	NM_052813.5	c.35G>A	p.Ser12Asn	missense_variant	2/13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.35G>A	p.Ser12Asn	missense_variant	2/13		NP_434701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.35G>A	p.Ser12Asn	missense_variant	2/13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.35G>A		non_coding_transcript_exon_variant	2/13			ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57732 AN: 151970 Hom.: 11398 Cov.: 34

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.356

GnomAD3 exomes AF: 0.406 AC: 101503 AN: 249730 Hom.: 21442 AF XY: 0.398 AC XY: 53936 AN XY: 135474

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.326

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.416 AC: 607140 AN: 1460408 Hom.: 128624 Cov.: 83 AF XY: 0.412 AC XY: 299118 AN XY: 726504

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.535

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.319

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.380 AC: 57801 AN: 152088 Hom.: 11416 Cov.: 34 AF XY: 0.378 AC XY: 28109 AN XY: 74352

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.358

Alfa AF: 0.404 Hom.: 23299

Bravo AF: 0.378

TwinsUK AF: 0.429 AC: 1591

ALSPAC AF: 0.436 AC: 1679

ESP6500AA AF: 0.278 AC: 1227

ESP6500EA AF: 0.422 AC: 3625

ExAC AF: 0.399 AC: 48444

Asia WGS AF: 0.388 AC: 1350 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.407

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Predisposition to invasive fungal disease due to CARD9 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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 76% of patients studied by a panel of primary immunodeficiencies. Number of patients: 67. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.30
DANN	Benign	0.90
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.000019	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.010
Sift	Benign	0.20	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0020	B;B
Vest4		0.021
MPC		0.63
ClinPred		0.0044	T
GERP RS		-0.55
Varity_R		0.11
gMVP		0.14

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: rs4077515; hg19: chr9-139266496; COSMIC: COSV53731725; COSMIC: COSV53731725;