19-48211856-C-T

Variant names:

• chr19-48211856-C-T
• rs749876926
• NM_001184900.3:c.1468G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001184900.3(CARD8):​c.1468G>A​(p.Glu490Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.802
• Publications: 1 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)

ENSG00000268583 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07216099).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184900.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD8	NM_001184900.3	MANE Select	c.1468G>A	p.Glu490Lys	missense	Exon 14 of 14	NP_001171829.1	Q9Y2G2-5
	CARD8	NM_001351782.2		c.1468G>A	p.Glu490Lys	missense	Exon 15 of 15	NP_001338711.1	Q9Y2G2-5
	CARD8	NM_001184901.1		c.1318G>A	p.Glu440Lys	missense	Exon 11 of 11	NP_001171830.1	Q9Y2G2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD8	ENST00000651546.1	MANE Select	c.1468G>A	p.Glu490Lys	missense	Exon 14 of 14	ENSP00000499211.1	Q9Y2G2-5
	CARD8	ENST00000391898.7	TSL:1	c.1468G>A	p.Glu490Lys	missense	Exon 11 of 11	ENSP00000375767.3	Q9Y2G2-5
	CARD8	ENST00000520153.5	TSL:1	c.1318G>A	p.Glu440Lys	missense	Exon 12 of 12	ENSP00000428736.1	Q9Y2G2-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251432 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.80
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.034
Sift	Benign	0.26	T
Sift4G	Uncertain	0.024	D
Vest4		0.11
MVP		0.13
MPC		0.53
ClinPred		0.35	T
GERP RS		-0.28
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs749876926; hg19: chr19-48715113; COSMIC: COSV62872770; COSMIC: COSV62872770;