rs200741645

Variant names:

• chr7-2913278-G-A
• rs200741645
• NM_032415.7:c.3019+9C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-2913278-G-A
• chr7-2913278-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032415.7(CARD11):​c.3019+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,594,558 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: CARD11 NM_032415.7 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.617
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• immunodeficiency 11b with atopic dermatitis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• severe combined immunodeficiency due to CARD11 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-2913278-G-A is Benign according to our data. Variant chr7-2913278-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540987.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (224/152192) while in subpopulation NFE AF = 0.00222 (151/67996). AF 95% confidence interval is 0.00193. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	NM_032415.7	MANE Select	c.3019+9C>T		intron	N/A	NP_115791.3
	CARD11	NM_001324281.3		c.3019+9C>T		intron	N/A	NP_001311210.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD11	ENST00000396946.9	TSL:1 MANE Select	c.3019+9C>T		intron	N/A	ENSP00000380150.4
	CARD11	ENST00000698637.1		n.4129+9C>T		intron	N/A
	CARD11	ENST00000698652.1		n.1975+9C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00135 AC: 313 AN: 232496 AF XY: 0.00129

Gnomad AFR exome AF: 0.000394

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.000870

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00162 AC: 2336 AN: 1442366 Hom.: 5 Cov.: 32 AF XY: 0.00163 AC XY: 1165 AN XY: 715934

African (AFR) AF: 0.000180 AC: 6 AN: 33272

American (AMR) AF: 0.000181 AC: 8 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.000902 AC: 23 AN: 25496

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39488

South Asian (SAS) AF: 0.0000353 AC: 3 AN: 85094

European-Finnish (FIN) AF: 0.00391 AC: 178 AN: 45574

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5696

European-Non Finnish (NFE) AF: 0.00186 AC: 2054 AN: 1103864

Other (OTH) AF: 0.00101 AC: 60 AN: 59694

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74414

African (AFR) AF: 0.000385 AC: 16 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00120

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	CARD11-related disorder (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
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.39
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs200741645; hg19: chr7-2952912; COSMIC: COSV105334079;