NM_032415.7:c.3019+9C>T

Variant names:

• chr7-2913278-G-A
• rs200741645
• NM_032415.7:c.3019+9C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_032415.7(CARD11):​c.3019+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,594,558 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: CARD11 NM_032415.7 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.617

Genes affected

CARD11 (HGNC:16393): (caspase recruitment domain family member 11) The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00147 (224/152192) while in subpopulation NFE AF= 0.00222 (151/67996). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD11	NM_032415.7	c.3019+9C>T		intron_variant	Intron 22 of 24	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3	c.3019+9C>T		intron_variant	Intron 23 of 25		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9	c.3019+9C>T		intron_variant	Intron 22 of 24	1	NM_032415.7	ENSP00000380150.4
CARD11	ENST00000698637.1	n.4129+9C>T		intron_variant	Intron 21 of 23
CARD11	ENST00000698652.1	n.1975+9C>T		intron_variant	Intron 5 of 7

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00135 AC: 313 AN: 232496 Hom.: 0 AF XY: 0.00129 AC XY: 164 AN XY: 127082

Gnomad AFR exome AF: 0.000394

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.000870

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00162 AC: 2336 AN: 1442366 Hom.: 5 Cov.: 32 AF XY: 0.00163 AC XY: 1165 AN XY: 715934

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.000902

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00391

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74414

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00120

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Apr 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CARD11 c.3019+9C>T variant (rs200741645) is reported in the literature in an individual with suspected primary immune deficiency (Morup 2022). This variant is reported in ClinVar (Variation ID: 540987) and is found in the non-Finnish European population with an allele frequency of 0.2% (241/121,146 alleles) in the Genome Aggregation Database (v2.1.1). This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic donor splice site. While the high population frequency suggests that this is likely a benign variant for the autosomal dominant disorders, the significance of this variant cannot be determined for the autosomal recessive disorder. Due to limited information, the significance of this variant is uncertain at this time. References: Morup SB et al. Added Value of Reanalysis of Whole Exome- and Whole Genome Sequencing Data From Patients Suspected of Primary Immune Deficiency Using an Extended Gene Panel and Structural Variation Calling. Front Immunol. 2022 Jun 30;13:906328. PMID: 35874679. -

Mar 30, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 19, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CARD11 gene demonstrated a sequence change in intron 22, c.3019+9C>T. This change does not appear to have been previously described in patients with CARD11-related disorders and has been described in the gnomAD with a relatively high population frequency of 0.20% in the non-Finnish European subpopulation (dbSNP rs200741645). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the CARD11 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. It is possible that this sequence change represents a benign sequence change in the CARD11 gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined. -

Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CARD11-related disorder Benign:1

Feb 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs200741645; hg19: chr7-2952912; COSMIC: COSV105334079; COSMIC: COSV105334079;