rs41454944

chr7-2928657-G-Achr7-2928657-G-Cchr7-2928657-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032415.7(CARD11):c.1695C>T(p.Ala565=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,158 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (98 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (125 hom.)
• Consequence: CARD11 NM_032415.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.18

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-2928657-G-A is Benign according to our data. Variant chr7-2928657-G-A is described in ClinVar as [Benign]. Clinvar id is 473929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD11	NM_032415.7	c.1695C>T	p.Ala565=	synonymous_variant	13/25	ENST00000396946.9
CARD11	NM_001324281.3	c.1695C>T	p.Ala565=	synonymous_variant	14/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD11	ENST00000396946.9	c.1695C>T	p.Ala565=	synonymous_variant	13/25	1	NM_032415.7	P1
CARD11	ENST00000355508.3	c.108C>T	p.Ala36=	synonymous_variant	2/7	3
CARD11	ENST00000698637.1	n.2021C>T		non_coding_transcript_exon_variant	13/24

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3158 AN: 152176 Hom.: 97 Cov.: 33

Gnomad AFR AF: 0.0712

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00608 AC: 1521 AN: 250320 Hom.: 57 AF XY: 0.00461 AC XY: 624 AN XY: 135418

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00242 AC: 3537 AN: 1460864 Hom.: 125 Cov.: 32 AF XY: 0.00216 AC XY: 1567 AN XY: 726802

Gnomad4 AFR exome AF: 0.0791

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.0208 AC: 3166 AN: 152294 Hom.: 98 Cov.: 33 AF XY: 0.0213 AC XY: 1588 AN XY: 74462

Gnomad4 AFR AF: 0.0711

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00496 Hom.: 13

Bravo AF: 0.0240

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.30
Dann	Benign	0.76

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: rs41454944; hg19: chr7-2968291;