7-2906649-C-T

Variant names:

• chr7-2906649-C-T
• rs147422861
• NM_032415.7:c.3454G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032415.7(CARD11):​c.3454G>A​(p.Asp1152Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000419 in 1,613,378 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 7.20
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068109334).
• BP6: Variant 7-2906649-C-T is Benign according to our data. Variant chr7-2906649-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 133803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00201 (306/152388) while in subpopulation AFR AF = 0.00683 (284/41594). AF 95% confidence interval is 0.00618. There are 2 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.3454G>A	p.Asp1152Asn	missense	Exon 25 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.3454G>A	p.Asp1152Asn	missense	Exon 26 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.3454G>A	p.Asp1152Asn	missense	Exon 25 of 25	ENSP00000380150.4	Q9BXL7
	CARD11	ENST00000888804.1		c.3454G>A	p.Asp1152Asn	missense	Exon 25 of 25	ENSP00000558863.1
	CARD11	ENST00000888805.1		c.3454G>A	p.Asp1152Asn	missense	Exon 25 of 25	ENSP00000558864.1

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152270 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000579 AC: 145 AN: 250454 AF XY: 0.000413

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1460990 Hom.: 2 Cov.: 30 AF XY: 0.000217 AC XY: 158 AN XY: 726686

African (AFR) AF: 0.00774 AC: 259 AN: 33462

American (AMR) AF: 0.000581 AC: 26 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111542

Other (OTH) AF: 0.000746 AC: 45 AN: 60356

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152388 Hom.: 2 Cov.: 33 AF XY: 0.00180 AC XY: 134 AN XY: 74512

African (AFR) AF: 0.00683 AC: 284 AN: 41594

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000617 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Severe combined immunodeficiency due to CARD11 deficiency;C4539957:Immunodeficiency 11b with atopic dermatitis;C4551967:BENTA disease (1)
-	-	1	Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.13	T
Polyphen		0.86	P
Vest4		0.32
MVP		0.49
MPC		0.61
ClinPred		0.037	T
GERP RS		3.8
Varity_R		0.16
gMVP		0.43
Mutation Taster		=90/10	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: rs147422861; hg19: chr7-2946283; COSMIC: COSV107504974;