chr9-136372011-G-T

Variant names:

• chr9-136372011-G-T
• rs775267971
• NM_052813.5:c.68C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_052813.5(CARD9):​c.68C>A​(p.Ser23*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CARD9 NM_052813.5 stop_gained
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 2.12
• Publications: 3 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_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052813.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	NM_052813.5	MANE Select	c.68C>A	p.Ser23*	stop_gained	Exon 2 of 13	NP_434700.2
	CARD9	NM_052814.4		c.68C>A	p.Ser23*	stop_gained	Exon 2 of 13	NP_434701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	ENST00000371732.10	TSL:1 MANE Select	c.68C>A	p.Ser23*	stop_gained	Exon 2 of 13	ENSP00000360797.5
	CARD9	ENST00000556340.1	TSL:1	n.199C>A		non_coding_transcript_exon	Exon 2 of 4
	ENSG00000289701	ENST00000696169.1		n.68C>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000512460.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 34

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jul 27, 2022

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.71	D
PhyloP100		2.1
Vest4		0.41
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=10/190	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs775267971; hg19: chr9-139266463;