rs78443994

chr7-2923299-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_032415.7(CARD11):c.1975G>A(p.Val659Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,605,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CARD11 NM_032415.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.0570

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CARD11
• BP4: Computational evidence support a benign effect (MetaRNN=0.009144366).
• BP6: Variant 7-2923299-C-T is Benign according to our data. Variant chr7-2923299-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7	c.1975G>A	p.Val659Met	missense_variant	16/25	ENST00000396946.9
CARD11	NM_001324281.3	c.1975G>A	p.Val659Met	missense_variant	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9	c.1975G>A	p.Val659Met	missense_variant	16/25	1	NM_032415.7	P1
CARD11	ENST00000355508.3	c.388G>A	p.Val130Met	missense_variant	5/7	3
CARD11	ENST00000698637.1	n.2301G>A		non_coding_transcript_exon_variant	16/24

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152058 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000232 AC: 56 AN: 241368 Hom.: 0 AF XY: 0.000167 AC XY: 22 AN XY: 131864

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.0000623

Gnomad NFE exome AF: 0.0000543

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1453218 Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 88 AN XY: 723188

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00280

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000436

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152176 Hom.: 0 Cov.: 34 AF XY: 0.000672 AC XY: 50 AN XY: 74400

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000228 Hom.: 1

Bravo AF: 0.000646

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to CARD11 deficiency;C4551967:BENTA disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.057
Sift	Benign	0.15	T;T
Sift4G	Benign	0.11	T;.
Polyphen		0.47	P;.
Vest4		0.093
MVP		0.51
MPC		0.47
ClinPred		0.0059	T
GERP RS		1.6
Varity_R		0.028
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs78443994; hg19: chr7-2962933; COSMIC: COSV62755667; COSMIC: COSV62755667;