9-136364321-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_052813.5(CARD9):c.1592C>T(p.Thr531Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T531T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CARD9 NM_052813.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Phosphothreonine; by CK2 (size 0) in uniprot entity CARD9_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD9	NM_052813.5	c.1592C>T	p.Thr531Ile	missense_variant	13/13	ENST00000371732.10
LOC124902309	XR_007061863.1	n.84+869G>A		intron_variant, non_coding_transcript_variant
CARD9	NM_052814.4	c.1442-159C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD9	ENST00000371732.10	c.1592C>T	p.Thr531Ile	missense_variant	13/13	1	NM_052813.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1410334 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 697060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CARD9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 531 of the CARD9 protein (p.Thr531Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.078		Loss of phosphorylation at T531 (P = 0.0165);
MVP		0.66
MPC		0.42
ClinPred		0.98	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.71

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: rs1358233637; hg19: chr9-139258773;