rs199705831

chr7-2913281-G-Achr7-2913281-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032415.7(CARD11):c.3019+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,591,864 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: CARD11 NM_032415.7 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00009933
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.512

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=-0.8).
• BP6: Variant 7-2913281-G-A is Benign according to our data. Variant chr7-2913281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 473932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00399 (602/150938) while in subpopulation AMR AF= 0.00962 (145/15070). AF 95% confidence interval is 0.00835. There are 4 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7	c.3019+6C>T		splice_donor_region_variant, intron_variant		ENST00000396946.9
CARD11	NM_001324281.3	c.3019+6C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9	c.3019+6C>T		splice_donor_region_variant, intron_variant		1	NM_032415.7	P1
CARD11	ENST00000698637.1	n.4129+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant
CARD11	ENST00000698652.1	n.1975+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 603 AN: 150820 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00970

Gnomad ASJ AF: 0.00868

Gnomad EAS AF: 0.00158

Gnomad SAS AF: 0.000839

Gnomad FIN AF: 0.00426

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.00537

GnomAD3 exomes AF: 0.00596 AC: 1408 AN: 236438 Hom.: 6 AF XY: 0.00510 AC XY: 658 AN XY: 129088

Gnomad AFR exome AF: 0.000707

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.00593

Gnomad EAS exome AF: 0.000442

Gnomad SAS exome AF: 0.000972

Gnomad FIN exome AF: 0.00535

Gnomad NFE exome AF: 0.00487

Gnomad OTH exome AF: 0.00626

GnomAD4 exome AF: 0.00423 AC: 6096 AN: 1440926 Hom.: 18 Cov.: 32 AF XY: 0.00409 AC XY: 2925 AN XY: 715704

Gnomad4 AFR exome AF: 0.000721

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.00696

Gnomad4 EAS exome AF: 0.000908

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00577

Gnomad4 NFE exome AF: 0.00415

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00399 AC: 602 AN: 150938 Hom.: 4 Cov.: 32 AF XY: 0.00367 AC XY: 271 AN XY: 73792

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00962

Gnomad4 ASJ AF: 0.00868

Gnomad4 EAS AF: 0.00158

Gnomad4 SAS AF: 0.000840

Gnomad4 FIN AF: 0.00426

Gnomad4 NFE AF: 0.00467

Gnomad4 OTH AF: 0.00531

Alfa AF: 0.00574 Hom.: 1

Bravo AF: 0.00464

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 23, 2019

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

CARD11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.5
Dann	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.0020
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: rs199705831; hg19: chr7-2952915; COSMIC: COSV67797516; COSMIC: COSV67797516;