NM_032415.7:c.2578G>A

Variant names:

• chr7-2918520-C-T
• rs368181734
• NM_032415.7:c.2578G>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.2578G>A​(p.Gly860Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,551,554 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G860G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.519
• Publications: 1 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=0.0024881363).
• BP6: Variant 7-2918520-C-T is Benign according to our data. Variant chr7-2918520-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 434566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00021 (32/152340) while in subpopulation SAS AF = 0.00518 (25/4828). AF 95% confidence interval is 0.0036. There are 2 homozygotes in GnomAd4. There are 22 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.2578G>A	p.Gly860Ser	missense	Exon 19 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.2578G>A	p.Gly860Ser	missense	Exon 20 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.2578G>A	p.Gly860Ser	missense	Exon 19 of 25	ENSP00000380150.4	Q9BXL7
	CARD11	ENST00000888804.1		c.2578G>A	p.Gly860Ser	missense	Exon 19 of 25	ENSP00000558863.1
	CARD11	ENST00000888805.1		c.2578G>A	p.Gly860Ser	missense	Exon 19 of 25	ENSP00000558864.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000713 AC: 111 AN: 155672 AF XY: 0.000926

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000874

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000669

Gnomad OTH exome AF: 0.000454

GnomAD4 exome AF: 0.000322 AC: 450 AN: 1399214 Hom.: 5 Cov.: 31 AF XY: 0.000456 AC XY: 315 AN XY: 690162

African (AFR) AF: 0.0000316 AC: 1 AN: 31626

American (AMR) AF: 0.00 AC: 0 AN: 35722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000558 AC: 2 AN: 35842

South Asian (SAS) AF: 0.00445 AC: 353 AN: 79252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48802

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5690

European-Non Finnish (NFE) AF: 0.0000778 AC: 84 AN: 1079090

Other (OTH) AF: 0.000138 AC: 8 AN: 58008

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74500

African (AFR) AF: 0.0000481 AC: 2 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.000570 AC: 48

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.14
DANN	Benign	0.49
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.52
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.23
MPC		0.45
ClinPred		0.0020	T
GERP RS		-7.1
Varity_R		0.013
gMVP		0.38
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368181734; hg19: chr7-2958154; COSMIC: COSV100829105; COSMIC: COSV100829105;