rs11881179

Positions:

• chr19-48231685-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.040 (391 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (335 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CARD8	NM_001184900.3	c.517A>G	p.Ile173Val	missense_variant	8/14	ENST00000651546.1	NP_001171829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD8	ENST00000651546.1	c.517A>G	p.Ile173Val	missense_variant	8/14		NM_001184900.3	ENSP00000499211	A2

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6074 AN: 152112 Hom.: 392 Cov.: 32

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

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.: 31 AF XY: 0.00548 AC XY: 3969 AN XY: 724030

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.: 32 AF XY: 0.0395 AC XY: 2943 AN XY: 74430

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: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.126 AC: 556

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0150 AC: 1823

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
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	N
LIST_S2	Benign	0.55	T;T;.;.;T;.;.
MetaRNN	Benign	0.0034	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs11881179; hg19: chr19-48734942; COSMIC: COSV62874025; COSMIC: COSV62874025;