9-136372044-C-T

Variant names:

• chr9-136372044-C-T
• rs4077515
• NM_052813.5:c.35G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S12S) has been classified as Likely 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
• Publications: 208 publications found

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 Gene-Disease associations (from GenCC):

• deep dermatophytosis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• predisposition to invasive fungal disease due to CARD9 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000289701 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 365858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5	c.35G>A	p.Ser12Asn	missense_variant	Exon 2 of 13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.35G>A	p.Ser12Asn	missense_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.35G>A	p.Ser12Asn	missense_variant	Exon 2 of 13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.35G>A		non_coding_transcript_exon_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.406 AC: 101503 AN: 249730 AF XY: 0.398

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 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

African (AFR) AF: 0.278 AC: 9321 AN: 33478

American (AMR) AF: 0.535 AC: 23919 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9232 AN: 26130

East Asian (EAS) AF: 0.319 AC: 12652 AN: 39684

South Asian (SAS) AF: 0.319 AC: 27548 AN: 86258

European-Finnish (FIN) AF: 0.417 AC: 21744 AN: 52084

Middle Eastern (MID) AF: 0.239 AC: 1379 AN: 5766

European-Non Finnish (NFE) AF: 0.429 AC: 477460 AN: 1111934

Other (OTH) AF: 0.396 AC: 23885 AN: 60370

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

African (AFR) AF: 0.288 AC: 11965 AN: 41484

American (AMR) AF: 0.475 AC: 7257 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1233 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1592 AN: 5154

South Asian (SAS) AF: 0.327 AC: 1580 AN: 4832

European-Finnish (FIN) AF: 0.410 AC: 4347 AN: 10594

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28637 AN: 67952

Other (OTH) AF: 0.358 AC: 756 AN: 2112

Alfa AF: 0.407 Hom.: 48433

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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
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
PhyloP100		-0.14
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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