19-48233449-G-A

Variant names:

• chr19-48233449-G-A
• rs4802449
• NM_001184900.3:c.350+954C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• inflammatory bowel disease 30

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CARD8	NM_001184900.3	c.350+954C>T		intron_variant	Intron 6 of 13	ENST00000651546.1	NP_001171829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD8	ENST00000651546.1	c.350+954C>T		intron_variant	Intron 6 of 13		NM_001184900.3	ENSP00000499211.1

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

GnomAD2 exomes AF: 0.367 AC: 46855 AN: 127748 AF XY: 0.365

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 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

African (AFR) AF: 0.513 AC: 4387 AN: 8554

American (AMR) AF: 0.452 AC: 12260 AN: 27152

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 3583 AN: 10746

East Asian (EAS) AF: 0.246 AC: 2259 AN: 9184

South Asian (SAS) AF: 0.403 AC: 24033 AN: 59660

European-Finnish (FIN) AF: 0.269 AC: 3321 AN: 12352

Middle Eastern (MID) AF: 0.303 AC: 844 AN: 2782

European-Non Finnish (NFE) AF: 0.332 AC: 52734 AN: 158654

Other (OTH) AF: 0.348 AC: 4937 AN: 14188

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

African (AFR) AF: 0.518 AC: 21493 AN: 41464

American (AMR) AF: 0.413 AC: 6303 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1158 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1311 AN: 5180

South Asian (SAS) AF: 0.416 AC: 2005 AN: 4816

European-Finnish (FIN) AF: 0.253 AC: 2671 AN: 10558

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22829 AN: 68002

Other (OTH) AF: 0.380 AC: 800 AN: 2108

Alfa AF: 0.355 Hom.: 38872

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
PhyloP100		-0.058
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4802449; hg19: chr19-48736706; COSMIC: COSV62874944; COSMIC: COSV62874944;