9-136364010-A-G

Variant names:

• chr9-136364010-A-G
• rs1135314
• ENST00000696169.1:n.*1531T>C

Variant summary

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

The ENST00000696169.1(ENSG00000289701):​n.*1531T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,296,282 control chromosomes in the GnomAD database, including 69,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7620 hom., cov: 35)
  • Exomes 𝑓: 0.32 (61685 hom.)
• Consequence: ENSG00000289701 ENST00000696169.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0790
• Publications: 27 publications found

Genes affected

ENSG00000289701 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-136364010-A-G is Benign according to our data. Variant chr9-136364010-A-G is described in ClinVar as [Benign]. Clinvar id is 365828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD9	NM_052813.5	c.*292T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.*115T>C		3_prime_UTR_variant	Exon 13 of 13		NP_434701.1
LOC124902309	XR_007061863.1	n.84+558A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289701	ENST00000696169.1	n.*1531T>C		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000512460.1
CARD9	ENST00000371732.10	c.*292T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.*1531T>C		3_prime_UTR_variant	Exon 12 of 13			ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46890 AN: 152100 Hom.: 7606 Cov.: 35

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.319 AC: 47626 AN: 149294 AF XY: 0.309

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.0436

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.322 AC: 367936 AN: 1144066 Hom.: 61685 Cov.: 16 AF XY: 0.318 AC XY: 183053 AN XY: 575504

African (AFR) AF: 0.260 AC: 6906 AN: 26604

American (AMR) AF: 0.458 AC: 16203 AN: 35402

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 9980 AN: 23586

East Asian (EAS) AF: 0.0928 AC: 3216 AN: 34650

South Asian (SAS) AF: 0.239 AC: 17693 AN: 74102

European-Finnish (FIN) AF: 0.319 AC: 15141 AN: 47422

Middle Eastern (MID) AF: 0.319 AC: 1671 AN: 5246

European-Non Finnish (NFE) AF: 0.332 AC: 281479 AN: 847432

Other (OTH) AF: 0.315 AC: 15647 AN: 49622

GnomAD4 genome AF: 0.308 AC: 46942 AN: 152216 Hom.: 7620 Cov.: 35 AF XY: 0.307 AC XY: 22838 AN XY: 74440

African (AFR) AF: 0.256 AC: 10656 AN: 41544

American (AMR) AF: 0.420 AC: 6419 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1445 AN: 3470

East Asian (EAS) AF: 0.0554 AC: 287 AN: 5184

South Asian (SAS) AF: 0.225 AC: 1087 AN: 4834

European-Finnish (FIN) AF: 0.309 AC: 3276 AN: 10598

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22595 AN: 67976

Other (OTH) AF: 0.337 AC: 711 AN: 2112

Alfa AF: 0.340 Hom.: 4012

Bravo AF: 0.313

Asia WGS AF: 0.188 AC: 654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 75% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Predisposition to invasive fungal disease due to CARD9 deficiency Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.45
PhyloP100		-0.079
PromoterAI		0.025	Neutral
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: rs1135314; hg19: chr9-139258462; COSMIC: COSV52517499; COSMIC: COSV52517499;