NM_052813.5:c.1153G>C

Variant names:

• chr9-136367753-C-G
• rs3124993
• NM_052813.5:c.1153G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_052813.5(CARD9):​c.1153G>C​(p.Val385Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,605,422 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 34)
  • Exomes 𝑓: 0.021 (390 hom.)
• Consequence: CARD9 NM_052813.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.106
• Publications: 12 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 -16 ACMG points.

• BP6: Variant 9-136367753-C-G is Benign according to our data. Variant chr9-136367753-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 365838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2031/152346) while in subpopulation NFE AF = 0.0231 (1573/68030). AF 95% confidence interval is 0.0222. There are 20 homozygotes in GnomAd4. There are 930 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.1153G>C	p.Val385Leu	missense	Exon 8 of 13	NP_434700.2
	CARD9	NM_052814.4		c.1153G>C	p.Val385Leu	missense	Exon 8 of 13	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.1153G>C	p.Val385Leu	missense	Exon 8 of 13	ENSP00000360797.5	Q9H257-1
	ENSG00000289701	ENST00000696169.1		n.*200G>C		non_coding_transcript_exon	Exon 8 of 13	ENSP00000512460.1
	ENSG00000289701	ENST00000696169.1		n.*200G>C		3_prime_UTR	Exon 8 of 13	ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2031 AN: 152228 Hom.: 20 Cov.: 34

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0145 AC: 3453 AN: 237458 AF XY: 0.0153

Gnomad AFR exome AF: 0.00447

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.0209 AC: 30329 AN: 1453076 Hom.: 390 Cov.: 31 AF XY: 0.0208 AC XY: 15027 AN XY: 723250

African (AFR) AF: 0.00356 AC: 119 AN: 33460

American (AMR) AF: 0.00408 AC: 182 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0121 AC: 1042 AN: 86130

European-Finnish (FIN) AF: 0.0123 AC: 561 AN: 45498

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5766

European-Non Finnish (NFE) AF: 0.0246 AC: 27305 AN: 1111528

Other (OTH) AF: 0.0165 AC: 997 AN: 60280

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152346 Hom.: 20 Cov.: 34 AF XY: 0.0125 AC XY: 930 AN XY: 74488

African (AFR) AF: 0.00320 AC: 133 AN: 41584

American (AMR) AF: 0.00627 AC: 96 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0231 AC: 1573 AN: 68030

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0154 Hom.: 12

Bravo AF: 0.0123

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00479 AC: 21

ESP6500EA AF: 0.0216 AC: 185

ExAC AF: 0.0157 AC: 1891

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Predisposition to invasive fungal disease due to CARD9 deficiency (2)
-	-	1	CARD9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.11
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.083
Sift	Benign	0.058	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.69
MutPred		0.15		Loss of MoRF binding (P = 0.0901)
MPC		0.078
ClinPred		0.0012	T
GERP RS		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.072
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -41

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

Other links and lift over

dbSNP: rs3124993; hg19: chr9-139262205;