9-136364346-C-G

Variant names:

• chr9-136364346-C-G
• rs144943839
• NM_052813.5:c.1567G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_052813.5(CARD9):​c.1567G>C​(p.Glu523Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00022 in 1,569,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E523D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CARD9 NM_052813.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.42
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18951592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5	c.1567G>C	p.Glu523Gln	missense_variant	Exon 13 of 13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.1442-184G>C		intron_variant	Intron 12 of 12		NP_434701.1
LOC124902309	XR_007061863.1	n.84+894C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.1567G>C	p.Glu523Gln	missense_variant	Exon 13 of 13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.*1195G>C		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000512460.1
ENSG00000289701	ENST00000696169.1	n.*1195G>C		3_prime_UTR_variant	Exon 12 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 22 AN: 181824 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 327 AN: 1416772 Hom.: 0 Cov.: 32 AF XY: 0.000248 AC XY: 174 AN XY: 700928

African (AFR) AF: 0.0000615 AC: 2 AN: 32532

American (AMR) AF: 0.000208 AC: 8 AN: 38502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.00 AC: 0 AN: 37656

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.000275 AC: 300 AN: 1090350

Other (OTH) AF: 0.000272 AC: 16 AN: 58776

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152232 Hom.: 0 Cov.: 34 AF XY: 0.000108 AC XY: 8 AN XY: 74364

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000592 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1567G>C (p.E523Q) alteration is located in exon 13 (coding exon 12) of the CARD9 gene. This alteration results from a G to C substitution at nucleotide position 1567, causing the glutamic acid (E) at amino acid position 523 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 523 of the CARD9 protein (p.Glu523Gln). This variant is present in population databases (rs144943839, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CARD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 646780). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.12
Sift	Benign	0.055	T
Sift4G	Uncertain	0.054	T
Polyphen		0.58	P
Vest4		0.13
MVP		0.64
MPC		0.20
ClinPred		0.061	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.14
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144943839; hg19: chr9-139258798;