9-136364350-GTCC-G

Position:

• chr9-136364350-GTCC-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BS1_Supporting

The NM_052813.5(CARD9):​c.1560_1562delGGA​(p.Glu520del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000363 in 1,570,322 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CARD9 NM_052813.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

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]

ENSG00000289701 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_052813.5. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000171 (26/152230) while in subpopulation AFR AF= 0.000579 (24/41462). AF 95% confidence interval is 0.000399. There are 1 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD9	NM_052813.5	c.1560_1562delGGA	p.Glu520del	disruptive_inframe_deletion	13/13	ENST00000371732.10	NP_434700.2
CARD9	NM_052814.4	c.1442-191_1442-189delGGA		intron_variant			NP_434701.1
LOC124902309	XR_007061863.1	n.84+905_84+907delTCC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD9	ENST00000371732.10	c.1560_1562delGGA	p.Glu520del	disruptive_inframe_deletion	13/13	1	NM_052813.5	ENSP00000360797.5
ENSG00000289701	ENST00000696169.1	n.*1188_*1190delGGA		non_coding_transcript_exon_variant	12/13			ENSP00000512460.1
ENSG00000289701	ENST00000696169.1	n.*1188_*1190delGGA		3_prime_UTR_variant	12/13			ENSP00000512460.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152230 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000271 AC: 5 AN: 184224 Hom.: 0 AF XY: 0.0000202 AC XY: 2 AN XY: 98894

Gnomad AFR exome AF: 0.000182

Gnomad AMR exome AF: 0.000107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 31 AN: 1418092 Hom.: 0 AF XY: 0.0000143 AC XY: 10 AN XY: 701696

Gnomad4 AFR exome AF: 0.000399

Gnomad4 AMR exome AF: 0.000103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000733

Gnomad4 OTH exome AF: 0.0000850

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152230 Hom.: 1 Cov.: 34 AF XY: 0.000215 AC XY: 16 AN XY: 74368

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000223

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This variant, c.1560_1562del, results in the deletion of 1 amino acid(s) of the CARD9 protein (p.Glu520del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs756632228, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with CARD9-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs756632228; hg19: chr9-139258802;