19-48211784-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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. 12/17 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: 0.000010 (0 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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]

ENSG00000268583 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14317608).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD8	NM_001184900.3	c.1540C>G	p.Leu514Val	missense_variant	Exon 14 of 14	ENST00000651546.1	NP_001171829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD8	ENST00000651546.1	c.1540C>G	p.Leu514Val	missense_variant	Exon 14 of 14		NM_001184900.3	ENSP00000499211.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1540C>G (p.L514V) alteration is located in exon 11 (coding exon 11) of the CARD8 gene. This alteration results from a C to G substitution at nucleotide position 1540, causing the leucine (L) at amino acid position 514 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T;.;.;.
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.58	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.14
MVP		0.12
MPC		0.63
ClinPred		0.44	T
GERP RS		2.0

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: rs749260047; hg19: chr19-48715041;