rs4802449

Positions:

• chr19-48233449-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001184900.3(CARD8):​c.350+954C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 455,348 control chromosomes in the GnomAD database, including 31,960 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12064 hom., cov: 33)
  • Exomes 𝑓: 0.36 (19896 hom.)
• Consequence: CARD8 NM_001184900.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD8	NM_001184900.3	c.350+954C>T		intron_variant		ENST00000651546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD8	ENST00000651546.1	c.350+954C>T		intron_variant			NM_001184900.3	A2

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58898 AN: 151958 Hom.: 12060 Cov.: 33

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.367 AC: 46855 AN: 127748 Hom.: 8935 AF XY: 0.365 AC XY: 25552 AN XY: 69992

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.403

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.357 AC: 108358 AN: 303272 Hom.: 19896 Cov.: 0 AF XY: 0.359 AC XY: 62058 AN XY: 172720

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.452

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.348

GnomAD4 genome AF: 0.388 AC: 58932 AN: 152076 Hom.: 12064 Cov.: 33 AF XY: 0.385 AC XY: 28640 AN XY: 74320

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.380

Alfa AF: 0.347 Hom.: 16319

Bravo AF: 0.403

Asia WGS AF: 0.337 AC: 1172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	10
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4802449; hg19: chr19-48736706; COSMIC: COSV62874944; COSMIC: COSV62874944;