7-2915275-G-C

Variant names:

• chr7-2915275-G-C
• rs775400791
• NM_032415.7:c.2801C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032415.7(CARD11):​c.2801C>G​(p.Ser934Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S934L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.09
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• immunodeficiency 11b with atopic dermatitis

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

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

ACMG classification

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, 0.762

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	NM_032415.7	MANE Select	c.2801C>G	p.Ser934Trp	missense	Exon 21 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.2801C>G	p.Ser934Trp	missense	Exon 22 of 26	NP_001311210.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	ENST00000396946.9	TSL:1 MANE Select	c.2801C>G	p.Ser934Trp	missense	Exon 21 of 25	ENSP00000380150.4
	CARD11	ENST00000698637.1		n.3911C>G		non_coding_transcript_exon	Exon 20 of 24
	CARD11	ENST00000698652.1		n.1757C>G		non_coding_transcript_exon	Exon 4 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.65
MutPred		0.43		Loss of disorder (P = 0.002)
MVP		0.34
MPC		1.5
ClinPred		0.92	D
GERP RS		4.5
Varity_R		0.11
gMVP		0.64
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs775400791; hg19: chr7-2954909;