9-136370446-G-T

Variant names:

• chr9-136370446-G-T
• rs200458322
• NM_052813.5:c.808-9C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_052813.5(CARD9):​c.808-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,609,710 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: CARD9 NM_052813.5 intron
• Scores: Splicing: ADA: 0.0004512
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0610
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-136370446-G-T is Benign according to our data. Variant chr9-136370446-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365845.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00154 (235/152348) while in subpopulation AMR AF = 0.00307 (47/15308). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	NM_052813.5	MANE Select	c.808-9C>A		intron	N/A	NP_434700.2
	CARD9	NM_052814.4		c.808-9C>A		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.808-9C>A		intron	N/A	ENSP00000360797.5
	ENSG00000289701	ENST00000696169.1		n.808-9C>A		intron	N/A	ENSP00000512460.1
	CARD9	ENST00000485975.1	TSL:2	n.309C>A		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00145 AC: 349 AN: 241510 AF XY: 0.00148

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000201

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00273

GnomAD4 exome AF: 0.00169 AC: 2469 AN: 1457362 Hom.: 5 Cov.: 33 AF XY: 0.00166 AC XY: 1205 AN XY: 724846

African (AFR) AF: 0.000270 AC: 9 AN: 33372

American (AMR) AF: 0.00232 AC: 103 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00111 AC: 95 AN: 85720

European-Finnish (FIN) AF: 0.000214 AC: 11 AN: 51420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5756

European-Non Finnish (NFE) AF: 0.00186 AC: 2065 AN: 1110860

Other (OTH) AF: 0.00173 AC: 104 AN: 60226

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152348 Hom.: 0 Cov.: 34 AF XY: 0.00166 AC XY: 124 AN XY: 74494

African (AFR) AF: 0.000409 AC: 17 AN: 41586

American (AMR) AF: 0.00307 AC: 47 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.00161

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Predisposition to invasive fungal disease due to CARD9 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.5
DANN	Benign	0.52
PhyloP100		-0.061
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.010		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: rs200458322; hg19: chr9-139264898;