9-136366634-A-G

Variant names:

• chr9-136366634-A-G
• rs10781496
• NM_052813.5:c.1357+166T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052813.5(CARD9):​c.1357+166T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 737,666 control chromosomes in the GnomAD database, including 67,295 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12121 hom., cov: 33)
  • Exomes 𝑓: 0.43 (55174 hom.)
• Consequence: CARD9 NM_052813.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.670
• Publications: 33 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

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.1357+166T>C		intron	N/A	NP_434700.2
	CARD9	NM_052814.4		c.1357+166T>C		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.1357+166T>C		intron	N/A	ENSP00000360797.5
	ENSG00000289701	ENST00000696169.1		n.*404+166T>C		intron	N/A	ENSP00000512460.1
	CARD9	ENST00000485975.1	TSL:2	n.1978T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59464 AN: 151984 Hom.: 12100 Cov.: 33

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.373

GnomAD4 exome AF: 0.429 AC: 251446 AN: 585564 Hom.: 55174 Cov.: 7 AF XY: 0.425 AC XY: 132917 AN XY: 312906

African (AFR) AF: 0.279 AC: 4539 AN: 16258

American (AMR) AF: 0.533 AC: 18474 AN: 34648

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 6081 AN: 16626

East Asian (EAS) AF: 0.330 AC: 11466 AN: 34738

South Asian (SAS) AF: 0.371 AC: 21723 AN: 58518

European-Finnish (FIN) AF: 0.467 AC: 17235 AN: 36936

Middle Eastern (MID) AF: 0.291 AC: 677 AN: 2330

European-Non Finnish (NFE) AF: 0.446 AC: 158219 AN: 354408

Other (OTH) AF: 0.419 AC: 13032 AN: 31102

GnomAD4 genome AF: 0.391 AC: 59529 AN: 152102 Hom.: 12121 Cov.: 33 AF XY: 0.391 AC XY: 29097 AN XY: 74350

African (AFR) AF: 0.281 AC: 11657 AN: 41492

American (AMR) AF: 0.469 AC: 7176 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1275 AN: 3462

East Asian (EAS) AF: 0.320 AC: 1655 AN: 5170

South Asian (SAS) AF: 0.383 AC: 1850 AN: 4824

European-Finnish (FIN) AF: 0.458 AC: 4849 AN: 10588

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29819 AN: 67956

Other (OTH) AF: 0.376 AC: 795 AN: 2112

Alfa AF: 0.420 Hom.: 15493

Bravo AF: 0.384

Asia WGS AF: 0.417 AC: 1453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.5
DANN	Benign	0.78
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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: rs10781496; hg19: chr9-139261086; COSMIC: COSV59996723; COSMIC: COSV59996723;