dbSNP rs11881179: CARD8:p.Ile173Val (chr19-48231685-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001184900.3(CARD8):c.517A>G(p.Ile173Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00895 in 1,608,068 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.040 ( 391 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 335 hom. )

Consequence

CARD8
NM_001184900.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.148

Variant links:

Genes affected

CARD8 (HGNC:17057): (caspase recruitment domain family member 8) The protein encoded by this gene belongs to the caspase recruitment domain (CARD)-containing family of proteins, which are involved in pathways leading to activation of caspases or nuclear factor kappa-B (NFKB). This protein may be a component of the inflammasome, a protein complex that plays a role in the activation of proinflammatory caspases. It is thought that this protein acts as an adaptor molecule that negatively regulates NFKB activation, CASP1-dependent IL1B secretion, and apoptosis. Polymorphisms in this gene may be associated with a susceptibility to rheumatoid arthritis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

CARD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034451187).

BP6

Variant 19-48231685-T-C is Benign according to our data. Variant chr19-48231685-T-C is described in ClinVar as [Benign]. Clinvar id is 1166621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD8	NM_001184900.3 link	c.517A>G	p.Ile173Val	missense_variant	Exon 8 of 14	ENST00000651546.1	NP_001171829.1	Q9Y2G2-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD8	ENST00000651546.1 link	c.517A>G	p.Ile173Val	missense_variant	Exon 8 of 14		NM_001184900.3	ENSP00000499211.1		Q9Y2G2-5

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6074

AN:

152112

Hom.:

392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.0626

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.0339

GnomAD3 exomes

AF:

0.0130

AC:

3216

AN:

247138

Hom.:

158

AF XY:

0.0108

AC XY:

1438

AN XY:

133738

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.00941

Gnomad ASJ exome

AF:

0.00731

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0118

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.00211

Gnomad OTH exome

AF:

0.00967

GnomAD4 exome

AF:

0.00571

AC:

8314

AN:

1455838

Hom.:

335

Cov.:

AF XY:

0.00548

AC XY:

3969

AN XY:

724030

show subpopulations

Gnomad4 AFR exome

AF:

0.130

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.00784

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.0000940

Gnomad4 NFE exome

AF:

0.00147

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.0399

AC:

6075

AN:

152230

Hom.:

391

Cov.:

AF XY:

0.0395

AC XY:

2943

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.0197

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00196

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.00935

Hom.:

147

Bravo

AF:

0.0458

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.126

AC:

556

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.0150

AC:

1823

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.34

DANN

Benign

0.24

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.55

T;T;.;.;T;.;.

MetaRNN

Benign

0.0034

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.36

PROVEAN

Benign

0.37

N;N;N;N;N;N;N

REVEL

Benign

0.014

Sift

Benign

0.57

T;T;.;T;.;T;T

Sift4G

Benign

0.094

T;T;T;T;T;T;T

Polyphen

0.36

.;.;B;.;B;.;.

Vest4

0.043

MPC

0.14

ClinPred

0.00037

GERP RS

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over