Genetic Variant NM_032415.7:c.645G>C (chr7-2944251-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032415.7(CARD11):c.645G>C(p.Lys215Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K215K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CARD11
NM_032415.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

Publications

0 publications found

Variant links:

COSMIC-nc: COSV62718953

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 links:

CARD11-AS1 (HGNC:40766): (CARD11 antisense RNA 1)

CARD11-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032415.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARD11	NM_032415.7	MANE Select	c.645G>C	p.Lys215Asn	missense	Exon 5 of 25	NP_115791.3
CARD11	NM_001324281.3		c.645G>C	p.Lys215Asn	missense	Exon 6 of 26	NP_001311210.1	Q9BXL7
CARD11-AS1	NR_187443.1		n.217C>G		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARD11	ENST00000396946.9	TSL:1 MANE Select	c.645G>C	p.Lys215Asn	missense	Exon 5 of 25	ENSP00000380150.4	Q9BXL7
CARD11-AS1	ENST00000423194.1	TSL:1	n.217C>G		non_coding_transcript_exon	Exon 1 of 2
CARD11	ENST00000888804.1		c.645G>C	p.Lys215Asn	missense	Exon 5 of 25	ENSP00000558863.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.7

PhyloP100

1.4

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.9

REVEL

Benign

0.24

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.82

MutPred

0.36

Loss of ubiquitination at K215 (P = 0.0027)

MVP

0.69

MPC

1.7

ClinPred

1.0

GERP RS

-3.1

Varity_R

0.83

gMVP

0.95

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over