19-48211784-G-C

Variant names:

• chr19-48211784-G-C
• rs749260047
• NM_001184900.3:c.1540C>G

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.1540C>G​(p.Leu514Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,874 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L514P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 2 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=0.14317608).

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.1540C>G	p.Leu514Val	missense	Exon 14 of 14	NP_001171829.1	Q9Y2G2-5
	CARD8	NM_001351782.2		c.1540C>G	p.Leu514Val	missense	Exon 15 of 15	NP_001338711.1	Q9Y2G2-5
	CARD8	NM_001184901.1		c.1390C>G	p.Leu464Val	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.1540C>G	p.Leu514Val	missense	Exon 14 of 14	ENSP00000499211.1	Q9Y2G2-5
	CARD8	ENST00000391898.7	TSL:1	c.1540C>G	p.Leu514Val	missense	Exon 11 of 11	ENSP00000375767.3	Q9Y2G2-5
	CARD8	ENST00000520153.5	TSL:1	c.1390C>G	p.Leu464Val	missense	Exon 12 of 12	ENSP00000428736.1	Q9Y2G2-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461874 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 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: 86258

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: 0.0000135 AC: 15 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000193 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Vest4		0.14
MVP		0.12
MPC		0.63
ClinPred		0.44	T
GERP RS		2.0
Mutation Taster		=82/18	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: rs749260047; hg19: chr19-48715041;