chr7-2944313-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_032415.7(CARD11):ā€‹c.583G>Cā€‹(p.Val195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.00016 ( 0 hom. )

Consequence

CARD11
NM_032415.7 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.56
Variant links:
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]
CARD11-AS1 (HGNC:40766): (CARD11 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03497976).
BP6
Variant 7-2944313-C-G is Benign according to our data. Variant chr7-2944313-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 957780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000163 (239/1461892) while in subpopulation AMR AF= 0.000313 (14/44724). AF 95% confidence interval is 0.000189. There are 0 homozygotes in gnomad4_exome. There are 125 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CARD11NM_032415.7 linkc.583G>C p.Val195Leu missense_variant 5/25 ENST00000396946.9 NP_115791.3 Q9BXL7A0A024R854Q8TES3
CARD11NM_001324281.3 linkc.583G>C p.Val195Leu missense_variant 6/26 NP_001311210.1 Q9BXL7A0A024R854Q8TES3
CARD11-AS1NR_187443.1 linkn.279C>G non_coding_transcript_exon_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CARD11ENST00000396946.9 linkc.583G>C p.Val195Leu missense_variant 5/251 NM_032415.7 ENSP00000380150.4 Q9BXL7

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152216
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000159
AC:
40
AN:
251494
Hom.:
0
AF XY:
0.000162
AC XY:
22
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
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:
0.000264
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000163
AC:
239
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.000172
AC XY:
125
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000186
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.000214
AC:
26
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 20, 2020DNA sequence analysis of the CARD11 gene demonstrated a sequence change, c.583G>C, in exon 5 that results in an amino acid change, p.Val195Leu. This sequence change has been described in the gnomAD database with a frequency of 0.024% in the European sub-population (dbSNP rs747351557). The p.Val195Leu change has been reported in the heterozygous state in a patient with atopic dermatitis, asthma, diverticulitis, and Type 2 diabetes (PMID: 30170123). In vitro studies demonstrated reduced protein activation, suggesting a loss of function mechanism (PMID: 30170123). The p.Val195Leu change affects a moderately conserved amino acid residue located in a domain of the CARD11 protein that is not known to be functional. The p.Val195Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Val195Leu change remains unknown at this time. -
BENTA disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 21, 2020This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 13, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
18
DANN
Benign
0.83
DEOGEN2
Benign
0.13
T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.47
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.77
T
M_CAP
Benign
0.0059
T
MetaRNN
Benign
0.035
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-1.2
N
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
0.92
N
REVEL
Benign
0.051
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.15
MutPred
0.13
Loss of methylation at K196 (P = 0.035);
MVP
0.26
MPC
0.97
ClinPred
0.053
T
GERP RS
1.8
Varity_R
0.041
gMVP
0.50

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747351557; hg19: chr7-2983947; COSMIC: COSV62719875; COSMIC: COSV62719875; API