7-2945952-C-G

Variant names:

• chr7-2945952-C-G
• rs10229368
• NM_032415.7:c.225G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_032415.7(CARD11):​c.225G>C​(p.Arg75Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,940 control chromosomes in the GnomAD database, including 1,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. R75R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (616 hom., cov: 32)
  • Exomes 𝑓: 0.016 (676 hom.)
• Consequence: CARD11 NM_032415.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.32
• 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-AS1 (HGNC:40766): (CARD11 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-2945952-C-G is Benign according to our data. Variant chr7-2945952-C-G is described in ClinVar as Benign. ClinVar VariationId is 473930.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

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.225G>C	p.Arg75Arg	synonymous	Exon 4 of 25	NP_115791.3
	CARD11	NM_001324281.3		c.225G>C	p.Arg75Arg	synonymous	Exon 5 of 26	NP_001311210.1
	CARD11-AS1	NR_187443.1		n.475-645C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	ENST00000396946.9	TSL:1 MANE Select	c.225G>C	p.Arg75Arg	synonymous	Exon 4 of 25	ENSP00000380150.4
	CARD11-AS1	ENST00000423194.1	TSL:1	n.475-645C>G		intron	N/A
	CARD11	ENST00000888804.1		c.225G>C	p.Arg75Arg	synonymous	Exon 4 of 25	ENSP00000558863.1

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8463 AN: 152094 Hom.: 612 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0212 AC: 5322 AN: 251296 AF XY: 0.0179

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0156 AC: 22850 AN: 1461728 Hom.: 676 Cov.: 32 AF XY: 0.0146 AC XY: 10625 AN XY: 727150

African (AFR) AF: 0.177 AC: 5910 AN: 33466

American (AMR) AF: 0.0152 AC: 678 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 446 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86238

European-Finnish (FIN) AF: 0.0140 AC: 748 AN: 53406

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5768

European-Non Finnish (NFE) AF: 0.0121 AC: 13475 AN: 1111920

Other (OTH) AF: 0.0232 AC: 1400 AN: 60390

GnomAD4 genome AF: 0.0558 AC: 8487 AN: 152212 Hom.: 616 Cov.: 32 AF XY: 0.0549 AC XY: 4084 AN XY: 74426

African (AFR) AF: 0.166 AC: 6885 AN: 41474

American (AMR) AF: 0.0271 AC: 414 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

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

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 868 AN: 68028

Other (OTH) AF: 0.0417 AC: 88 AN: 2112

Alfa AF: 0.0234 Hom.: 46

Bravo AF: 0.0618

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0110

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.9
DANN	Benign	0.60
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs10229368; hg19: chr7-2985586; COSMIC: COSV62717184;