NM_032415.7:c.3090C>A

Variant names:

• chr7-2912226-G-T
• rs112241277
• NM_032415.7:c.3090C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032415.7(CARD11):​c.3090C>A​(p.Asn1030Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1030N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14373699).

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.3090C>A	p.Asn1030Lys	missense	Exon 23 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.3090C>A	p.Asn1030Lys	missense	Exon 24 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.3090C>A	p.Asn1030Lys	missense	Exon 23 of 25	ENSP00000380150.4	Q9BXL7
	CARD11	ENST00000888804.1		c.3090C>A	p.Asn1030Lys	missense	Exon 23 of 25	ENSP00000558863.1
	CARD11	ENST00000888805.1		c.3090C>A	p.Asn1030Lys	missense	Exon 23 of 25	ENSP00000558864.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.061
Sift	Benign	0.74	T
Sift4G	Benign	0.64	T
Polyphen		0.044	B
Vest4		0.47
MutPred		0.54		Gain of methylation at N1030 (P = 0.0019)
MVP		0.40
MPC		0.77
ClinPred		0.88	D
GERP RS		2.3
Varity_R		0.082
gMVP		0.53
Mutation Taster		=67/33	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: rs112241277; hg19: chr7-2951860;