rs141992399

Variant names:

• chr9-136365140-C-G
• rs141992399
• NM_052813.5:c.1434+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-136365140-C-G
• chr9-136365140-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_052813.5(CARD9):​c.1434+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,612,174 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (18 hom.)
• Consequence: CARD9 NM_052813.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 1.57
• Publications: 21 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: Likely_benign. The variant received -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 9-136365140-C-G is Benign according to our data. Variant chr9-136365140-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 535816.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00372 (567/152338) while in subpopulation NFE AF = 0.00638 (434/68012). AF 95% confidence interval is 0.00589. There are 2 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1434+1G>C		splice_donor intron	N/A	NP_434700.2
	CARD9	NM_052814.4		c.1434+1G>C		splice_donor 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.1434+1G>C		splice_donor intron	N/A	ENSP00000360797.5	Q9H257-1
	ENSG00000289701	ENST00000696169.1		n.*482G>C		non_coding_transcript_exon	Exon 11 of 13	ENSP00000512460.1
	ENSG00000289701	ENST00000696169.1		n.*482G>C		3_prime_UTR	Exon 11 of 13	ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 567 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00327 AC: 812 AN: 248172 AF XY: 0.00335

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00722

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.000926

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00470 AC: 6860 AN: 1459836 Hom.: 18 Cov.: 31 AF XY: 0.00459 AC XY: 3334 AN XY: 726310

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 173 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86252

European-Finnish (FIN) AF: 0.00114 AC: 59 AN: 51658

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.00559 AC: 6214 AN: 1111820

Other (OTH) AF: 0.00346 AC: 209 AN: 60358

GnomAD4 genome AF: 0.00372 AC: 567 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00322 AC XY: 240 AN XY: 74498

African (AFR) AF: 0.000962 AC: 40 AN: 41580

American (AMR) AF: 0.00124 AC: 19 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68012

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00446 Hom.: 0

Bravo AF: 0.00369

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00322 AC: 390

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	Predisposition to invasive fungal disease due to CARD9 deficiency (5)
-	3	1	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Uncertain	0.47
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.25	N
PhyloP100		1.6
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=94/6	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141992399; hg19: chr9-139259592;