9-136371349-C-T

Variant names:

• chr9-136371349-C-T
• rs115131813
• NM_052813.5:c.297G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052813.5(CARD9):​c.297G>A​(p.Pro99Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,602,174 control chromosomes in the GnomAD database, including 838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (82 hom., cov: 34)
  • Exomes 𝑓: 0.020 (756 hom.)
• Consequence: CARD9 NM_052813.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.818
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-136371349-C-T is Benign according to our data. Variant chr9-136371349-C-T is described in ClinVar as Benign. ClinVar VariationId is 365853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.818 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0837 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.297G>A	p.Pro99Pro	synonymous	Exon 3 of 13	NP_434700.2
	CARD9	NM_052814.4		c.297G>A	p.Pro99Pro	synonymous	Exon 3 of 13	NP_434701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD9	ENST00000371732.10	TSL:1 MANE Select	c.297G>A	p.Pro99Pro	synonymous	Exon 3 of 13	ENSP00000360797.5
	CARD9	ENST00000556340.1	TSL:1	n.428G>A		non_coding_transcript_exon	Exon 3 of 4
	ENSG00000289701	ENST00000696169.1		n.297G>A		non_coding_transcript_exon	Exon 3 of 13	ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2921 AN: 152212 Hom.: 78 Cov.: 34

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0869

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0326 AC: 7451 AN: 228396 AF XY: 0.0269

Gnomad AFR exome AF: 0.00533

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0200 AC: 29002 AN: 1449844 Hom.: 756 Cov.: 34 AF XY: 0.0190 AC XY: 13712 AN XY: 720220

African (AFR) AF: 0.00420 AC: 140 AN: 33346

American (AMR) AF: 0.148 AC: 6404 AN: 43152

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 103 AN: 25848

East Asian (EAS) AF: 0.000688 AC: 27 AN: 39240

South Asian (SAS) AF: 0.00391 AC: 331 AN: 84548

European-Finnish (FIN) AF: 0.0178 AC: 909 AN: 51058

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5756

European-Non Finnish (NFE) AF: 0.0180 AC: 19980 AN: 1106976

Other (OTH) AF: 0.0181 AC: 1082 AN: 59920

GnomAD4 genome AF: 0.0193 AC: 2933 AN: 152330 Hom.: 82 Cov.: 34 AF XY: 0.0193 AC XY: 1436 AN XY: 74496

African (AFR) AF: 0.00556 AC: 231 AN: 41574

American (AMR) AF: 0.0876 AC: 1340 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0169 AC: 1147 AN: 68022

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0167 Hom.: 15

Bravo AF: 0.0254

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.69
DANN	Benign	0.90
PhyloP100		-0.82
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: rs115131813; hg19: chr9-139265801; COSMIC: COSV53739282; COSMIC: COSV53739282;