7-2923155-G-C

Variant names:

• chr7-2923155-G-C
• rs143049136
• NM_032415.7:c.2119C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032415.7(CARD11):​c.2119C>G​(p.Arg707Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R707C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• BENTA disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• immunodeficiency 11b with atopic dermatitis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• severe combined immunodeficiency due to CARD11 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	NM_032415.7	MANE Select	c.2119C>G	p.Arg707Gly	missense	Exon 16 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.2119C>G	p.Arg707Gly	missense	Exon 17 of 26	NP_001311210.1	Q9BXL7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	ENST00000396946.9	TSL:1 MANE Select	c.2119C>G	p.Arg707Gly	missense	Exon 16 of 25	ENSP00000380150.4	Q9BXL7
	CARD11	ENST00000888804.1		c.2119C>G	p.Arg707Gly	missense	Exon 16 of 25	ENSP00000558863.1
	CARD11	ENST00000888805.1		c.2119C>G	p.Arg707Gly	missense	Exon 16 of 25	ENSP00000558864.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	31
DANN	Benign	0.95
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.090	T
Polyphen		0.012	B
Vest4		0.37
MutPred		0.48		Loss of sheet (P = 0.0037)
MVP		0.55
MPC		0.75
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.66
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: 0
DS_DL_spliceai		0.23		Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143049136; hg19: chr7-2962789;