rs41396348

Positions:

• chr7-2934531-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000396946.9(CARD11):​c.1440G>A​(p.Ser480=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,132 control chromosomes in the GnomAD database, including 1,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.064 (998 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (946 hom.)
• Consequence: CARD11 ENST00000396946.9 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -5.99

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-2934531-C-T is Benign according to our data. Variant chr7-2934531-C-T is described in ClinVar as [Benign]. Clinvar id is 473928.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD11	NM_032415.7	c.1440G>A	p.Ser480=	synonymous_variant	10/25	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3	c.1440G>A	p.Ser480=	synonymous_variant	11/26		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9	c.1440G>A	p.Ser480=	synonymous_variant	10/25	1	NM_032415.7	ENSP00000380150	P1
CARD11	ENST00000698637.1	n.1766G>A		non_coding_transcript_exon_variant	10/24
CARD11	ENST00000698654.1	n.1699G>A		non_coding_transcript_exon_variant	10/10
CARD11	ENST00000698662.1	n.1640G>A		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.0640 AC: 9741 AN: 152156 Hom.: 997 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0511

GnomAD3 exomes AF: 0.0171 AC: 4287 AN: 251298 Hom.: 451 AF XY: 0.0126 AC XY: 1705 AN XY: 135836

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000889

Gnomad OTH exome AF: 0.00979

GnomAD4 exome AF: 0.00680 AC: 9935 AN: 1461858 Hom.: 946 Cov.: 31 AF XY: 0.00590 AC XY: 4290 AN XY: 727230

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000616

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0641 AC: 9758 AN: 152274 Hom.: 998 Cov.: 32 AF XY: 0.0624 AC XY: 4647 AN XY: 74462

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.0506

Alfa AF: 0.0261 Hom.: 213

Bravo AF: 0.0726

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

CARD11-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as 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	-0.85
CADD	Benign	0.12
DANN	Benign	0.77

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: rs41396348; hg19: chr7-2974165;