rs10781499

Variant names:

• chr9-136371953-G-A
• rs10781499
• NM_052813.5:c.126C>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.126C>T​(p.Pro42Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,609,980 control chromosomes in the GnomAD database, including 140,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11482 hom., cov: 34)
  • Exomes 𝑓: 0.42 (129058 hom.)
• Consequence: CARD9 NM_052813.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.07

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]

ENSG00000289701 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 9-136371953-G-A is Benign according to our data. Variant chr9-136371953-G-A is described in ClinVar as [Benign]. Clinvar id is 365857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136371953-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 2 of 13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 2 of 13		NP_434701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.126C>T	p.Pro42Pro	synonymous_variant	Exon 2 of 13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.126C>T		non_coding_transcript_exon_variant	Exon 2 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57880 AN: 152020 Hom.: 11464 Cov.: 34

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.357

GnomAD3 exomes AF: 0.407 AC: 102015 AN: 250490 Hom.: 21600 AF XY: 0.399 AC XY: 54106 AN XY: 135568

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.358

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.417 AC: 607724 AN: 1457842 Hom.: 129058 Cov.: 73 AF XY: 0.413 AC XY: 299109 AN XY: 724554

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.535

Gnomad4 ASJ exome AF: 0.355

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.381 AC: 57944 AN: 152138 Hom.: 11482 Cov.: 34 AF XY: 0.379 AC XY: 28175 AN XY: 74380

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.359

Alfa AF: 0.407 Hom.: 21366

Bravo AF: 0.379

Asia WGS AF: 0.385 AC: 1338 AN: 3478

EpiCase AF: 0.393

EpiControl AF: 0.408

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.2
DANN	Benign	0.91
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: rs10781499; hg19: chr9-139266405; COSMIC: COSV53732978; COSMIC: COSV53732978;