rs61757651

Positions:

• chr7-2913393-G-A
• chr7-2913393-G-C
• chr7-2913393-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_032415.7(CARD11):​c.2913C>T​(p.Cys971=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,612,090 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (5 hom.)
• Consequence: CARD11 NM_032415.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0470

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-2913393-G-A is Benign according to our data. Variant chr7-2913393-G-A is described in ClinVar as [Benign]. Clinvar id is 540977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.047 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00309 (471/152288) while in subpopulation AFR AF= 0.0102 (426/41574). AF 95% confidence interval is 0.00944. There are 3 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD11	NM_032415.7	c.2913C>T	p.Cys971=	synonymous_variant	22/25	ENST00000396946.9	NP_115791.3
CARD11	NM_001324281.3	c.2913C>T	p.Cys971=	synonymous_variant	23/26		NP_001311210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD11	ENST00000396946.9	c.2913C>T	p.Cys971=	synonymous_variant	22/25	1	NM_032415.7	ENSP00000380150	P1
CARD11	ENST00000698637.1	n.4023C>T		non_coding_transcript_exon_variant	21/24
CARD11	ENST00000698652.1	n.1869C>T		non_coding_transcript_exon_variant	5/8

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000935 AC: 233 AN: 249166 Hom.: 0 AF XY: 0.000674 AC XY: 91 AN XY: 135012

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000377 AC: 551 AN: 1459802 Hom.: 5 Cov.: 32 AF XY: 0.000362 AC XY: 263 AN XY: 726166

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000777

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74454

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.00351

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 14, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61757651; hg19: chr7-2953027; COSMIC: COSV101210775; COSMIC: COSV101210775;