rs2527509

chr7-2923119-G-Achr7-2923119-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032415.7(CARD11):c.2142+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,606,740 control chromosomes in the GnomAD database, including 440,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32710 hom., cov: 34)
  • Exomes 𝑓: 0.74 (407908 hom.)
• Consequence: CARD11 NM_032415.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.293

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-2923119-G-A is Benign according to our data. Variant chr7-2923119-G-A is described in ClinVar as [Benign]. Clinvar id is 402479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7	c.2142+13C>T		intron_variant		ENST00000396946.9
CARD11	NM_001324281.3	c.2142+13C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9	c.2142+13C>T		intron_variant		1	NM_032415.7	P1
CARD11	ENST00000355508.3	c.555+13C>T		intron_variant		3
CARD11	ENST00000698637.1	n.2468+13C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95577 AN: 152080 Hom.: 32712 Cov.: 34

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.642

GnomAD3 exomes AF: 0.676 AC: 164061 AN: 242524 Hom.: 57880 AF XY: 0.683 AC XY: 90314 AN XY: 132242

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.634

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.382

Gnomad SAS exome AF: 0.620

Gnomad FIN exome AF: 0.815

Gnomad NFE exome AF: 0.770

Gnomad OTH exome AF: 0.717

GnomAD4 exome AF: 0.742 AC: 1078948 AN: 1454542 Hom.: 407908 Cov.: 35 AF XY: 0.740 AC XY: 535119 AN XY: 723610

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.725

Gnomad4 EAS exome AF: 0.412

Gnomad4 SAS exome AF: 0.625

Gnomad4 FIN exome AF: 0.815

Gnomad4 NFE exome AF: 0.778

Gnomad4 OTH exome AF: 0.707

GnomAD4 genome AF: 0.628 AC: 95598 AN: 152198 Hom.: 32710 Cov.: 34 AF XY: 0.627 AC XY: 46637 AN XY: 74402

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.650

Gnomad4 ASJ AF: 0.729

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.602

Gnomad4 FIN AF: 0.820

Gnomad4 NFE AF: 0.771

Gnomad4 OTH AF: 0.638

Alfa AF: 0.719 Hom.: 9922

Bravo AF: 0.603

Asia WGS AF: 0.501 AC: 1741 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

BENTA disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Immunodeficiency 11b with atopic dermatitis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2019

- -

Severe combined immunodeficiency due to CARD11 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.4
Dann	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs2527509; hg19: chr7-2962753; COSMIC: COSV62755629; COSMIC: COSV62755629;