7-2937133-G-T

Variant names:

• chr7-2937133-G-T
• rs6945582
• NM_032415.7:c.1245C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_032415.7(CARD11):​c.1245C>A​(p.Asp415Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D415D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.431
• Publications: 22 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000145 (22/152152) while in subpopulation NFE AF = 0.000294 (20/68000). AF 95% confidence interval is 0.000194. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1245C>A	p.Asp415Glu	missense	Exon 9 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.1245C>A	p.Asp415Glu	missense	Exon 10 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.1245C>A	p.Asp415Glu	missense	Exon 9 of 25	ENSP00000380150.4	Q9BXL7
	CARD11	ENST00000888804.1		c.1245C>A	p.Asp415Glu	missense	Exon 9 of 25	ENSP00000558863.1
	CARD11	ENST00000888805.1		c.1245C>A	p.Asp415Glu	missense	Exon 9 of 25	ENSP00000558864.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251382 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000937 AC: 137 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.0000963 AC XY: 70 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000119 AC: 132 AN: 1112002

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 1039

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.43
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.13
Sift	Benign	0.30	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.89	P
Vest4		0.69
MutPred		0.20		Gain of methylation at K413 (P = 0.1645)
MVP		0.35
MPC		1.3
ClinPred		0.38	T
GERP RS		-0.61
Varity_R		0.32
gMVP		0.42
Mutation Taster		=77/23	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: rs6945582; hg19: chr7-2976767;