9-136372044-C-T

Variant names:

• chr9-136372044-C-T
• rs4077515
• NM_052813.5:c.35G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052813.5(CARD9):​c.35G>A​(p.Ser12Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,612,496 control chromosomes in the GnomAD database, including 140,040 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S12S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.38 (11416 hom., cov: 34)
  • Exomes 𝑓: 0.42 (128624 hom.)
• Consequence: CARD9 NM_052813.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.135
• Publications: 208 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8848918E-5).
• BP6: Variant 9-136372044-C-T is Benign according to our data. Variant chr9-136372044-C-T is described in ClinVar as Benign. ClinVar VariationId is 365858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.465 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	NM_052813.5	MANE Select	c.35G>A	p.Ser12Asn	missense	Exon 2 of 13	NP_434700.2
	CARD9	NM_052814.4		c.35G>A	p.Ser12Asn	missense	Exon 2 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.35G>A	p.Ser12Asn	missense	Exon 2 of 13	ENSP00000360797.5	Q9H257-1
	CARD9	ENST00000556340.1	TSL:1	n.166G>A		non_coding_transcript_exon	Exon 2 of 4
	ENSG00000289701	ENST00000696169.1		n.35G>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57732 AN: 151970 Hom.: 11398 Cov.: 34

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.356

GnomAD2 exomes AF: 0.406 AC: 101503 AN: 249730 AF XY: 0.398

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.416 AC: 607140 AN: 1460408 Hom.: 128624 Cov.: 83 AF XY: 0.412 AC XY: 299118 AN XY: 726504

African (AFR) AF: 0.278 AC: 9321 AN: 33478

American (AMR) AF: 0.535 AC: 23919 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9232 AN: 26130

East Asian (EAS) AF: 0.319 AC: 12652 AN: 39684

South Asian (SAS) AF: 0.319 AC: 27548 AN: 86258

European-Finnish (FIN) AF: 0.417 AC: 21744 AN: 52084

Middle Eastern (MID) AF: 0.239 AC: 1379 AN: 5766

European-Non Finnish (NFE) AF: 0.429 AC: 477460 AN: 1111934

Other (OTH) AF: 0.396 AC: 23885 AN: 60370

GnomAD4 genome AF: 0.380 AC: 57801 AN: 152088 Hom.: 11416 Cov.: 34 AF XY: 0.378 AC XY: 28109 AN XY: 74352

African (AFR) AF: 0.288 AC: 11965 AN: 41484

American (AMR) AF: 0.475 AC: 7257 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1233 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1592 AN: 5154

South Asian (SAS) AF: 0.327 AC: 1580 AN: 4832

European-Finnish (FIN) AF: 0.410 AC: 4347 AN: 10594

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28637 AN: 67952

Other (OTH) AF: 0.358 AC: 756 AN: 2112

Alfa AF: 0.407 Hom.: 48433

Bravo AF: 0.378

TwinsUK AF: 0.429 AC: 1591

ALSPAC AF: 0.436 AC: 1679

ESP6500AA AF: 0.278 AC: 1227

ESP6500EA AF: 0.422 AC: 3625

ExAC AF: 0.399 AC: 48444

Asia WGS AF: 0.388 AC: 1350 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.407

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.30
DANN	Benign	0.90
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.000019	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.14
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.010
Sift	Benign	0.20	T
Sift4G	Benign	0.53	T
Polyphen		0.0020	B
Vest4		0.021
MPC		0.63
ClinPred		0.0044	T
GERP RS		-0.55
Varity_R		0.11
gMVP		0.14
Mutation Taster		=97/3	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: rs4077515; hg19: chr9-139266496; COSMIC: COSV53731725; COSMIC: COSV53731725;