chr9-136364542-G-A

Variant names:

• chr9-136364542-G-A
• rs758540382
• NM_052813.5:c.1452C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_052813.5(CARD9):​c.1452C>T​(p.Ser484Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,386,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CARD9 NM_052813.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.270
• Publications: 0 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-136364542-G-A is Benign according to our data. Variant chr9-136364542-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 535817.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.27 with no splicing effect.

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.1452C>T	p.Ser484Ser	synonymous	Exon 12 of 13	NP_434700.2
	CARD9	NM_052814.4		c.1441+11C>T		intron	N/A	NP_434701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	ENST00000371732.10	TSL:1 MANE Select	c.1452C>T	p.Ser484Ser	synonymous	Exon 12 of 13	ENSP00000360797.5
	ENSG00000289701	ENST00000696169.1		n.*1080C>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000512460.1
	ENSG00000289701	ENST00000696169.1		n.*1080C>T		3_prime_UTR	Exon 11 of 13	ENSP00000512460.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1386524 Hom.: 0 Cov.: 32 AF XY: 0.00000292 AC XY: 2 AN XY: 684224

African (AFR) AF: 0.00 AC: 0 AN: 31548

American (AMR) AF: 0.0000280 AC: 1 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35754

South Asian (SAS) AF: 0.00 AC: 0 AN: 79158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078772

Other (OTH) AF: 0.00 AC: 0 AN: 57774

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758540382; hg19: chr9-139258994;