rs754404646

Variant names:

• chr9-136370283-TGC-T
• rs754404646
• NM_052813.5:c.951+9_951+10delGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_052813.5(CARD9):​c.951+9_951+10delGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,598,152 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 34)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: CARD9 NM_052813.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000289701 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 9-136370283-TGC-T is Benign according to our data. Variant chr9-136370283-TGC-T is described in ClinVar as Benign. ClinVar VariationId is 535818.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00626 (954/152336) while in subpopulation AFR AF = 0.0213 (885/41584). AF 95% confidence interval is 0.0201. There are 9 homozygotes in GnomAd4. There are 440 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	NM_052813.5	MANE Select	c.951+9_951+10delGC		intron	N/A	NP_434700.2
	CARD9	NM_052814.4		c.951+9_951+10delGC		intron	N/A	NP_434701.1	Q9H257-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	ENST00000371732.10	TSL:1 MANE Select	c.951+9_951+10delGC		intron	N/A	ENSP00000360797.5	Q9H257-1
	ENSG00000289701	ENST00000696169.1		n.951+9_951+10delGC		intron	N/A	ENSP00000512460.1
	CARD9	ENST00000892159.1		c.951+9_951+10delGC		intron	N/A	ENSP00000562218.1

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 952 AN: 152218 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.000608 AC: 139 AN: 228548 AF XY: 0.000494

Gnomad AFR exome AF: 0.00777

Gnomad AMR exome AF: 0.000654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000478

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000665 AC: 961 AN: 1445816 Hom.: 8 AF XY: 0.000521 AC XY: 375 AN XY: 719296

African (AFR) AF: 0.0225 AC: 748 AN: 33304

American (AMR) AF: 0.00197 AC: 87 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.0000587 AC: 5 AN: 85168

European-Finnish (FIN) AF: 0.0000233 AC: 1 AN: 42984

Middle Eastern (MID) AF: 0.000631 AC: 3 AN: 4758

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1109918

Other (OTH) AF: 0.00145 AC: 87 AN: 59950

GnomAD4 genome AF: 0.00626 AC: 954 AN: 152336 Hom.: 9 Cov.: 34 AF XY: 0.00591 AC XY: 440 AN XY: 74498

African (AFR) AF: 0.0213 AC: 885 AN: 41584

American (AMR) AF: 0.00359 AC: 55 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Predisposition to invasive fungal disease due to CARD9 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs754404646; hg19: chr9-139264735;