9-136364351-T-G

Variant names:

• chr9-136364351-T-G
• NM_052813.5:c.1562A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_052813.5(CARD9):​c.1562A>C​(p.Asp521Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CARD9 NM_052813.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5	c.1562A>C	p.Asp521Ala	missense_variant	Exon 13 of 13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.1442-189A>C		intron_variant	Intron 12 of 12		NP_434701.1
LOC124902309	XR_007061863.1	n.84+899T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.1562A>C	p.Asp521Ala	missense_variant	Exon 13 of 13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.*1190A>C		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000512460.1
ENSG00000289701	ENST00000696169.1	n.*1190A>C		3_prime_UTR_variant	Exon 12 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

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

Apr 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with alanine at codon 521 of the CARD9 protein (p.Asp521Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CARD9-related conditions. 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	0.14
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.67
MutPred		0.097		Gain of MoRF binding (P = 0.0413);
MVP		0.63
MPC		0.14
ClinPred		0.57	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-139258803;