19-48234449-A-G

Variant names:

• chr19-48234449-A-G
• rs2043211
• NM_001184900.3:c.304T>C
• CARD8 p.Phe102Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_001184900.3(CARD8):c.304T>C (p.Phe102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene CARD8 is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The gene CARD8 is a known oncogene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The gene CARD8 is a cancer driver gene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000899, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F102I: Benign (ClinVar VariationId 1166485, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 25 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)

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CARD8 NM_001184900.3	MANE Select	c.304T>C p.Phe102Leu	missense	Exon 6 of 14	Prot: NP_001171829.1 UniProt:
	CARD8 NM_001351782.2		c.304T>C p.Phe102Leu	missense	Exon 7 of 15	Prot: NP_001338711.1 UniProt:
	CARD8 NM_001184901.1		c.154T>C p.Phe52Leu	missense	Exon 3 of 11	Prot: NP_001171830.1 UniProt:

CARD8 NM_001184900.3

MANE Select

HGVSc / HGVSpc.304T>Cp.Phe102Leu

Exon rankExon 6 of 14

missense

Prot: NP_001171829.1UniProt: Q9Y2G2-5

CARD8 NM_001351782.2

HGVSc / HGVSpc.304T>Cp.Phe102Leu

Exon rankExon 7 of 15

missense

Prot: NP_001338711.1UniProt: Q9Y2G2-5

CARD8 NM_001184901.1

HGVSc / HGVSpc.154T>Cp.Phe52Leu

Exon rankExon 3 of 11

missense

Prot: NP_001171830.1UniProt: Q9Y2G2-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CARD8 ENST00000651546.1	MANE Select	c.304T>C p.Phe102Leu	missense	Exon 6 of 14	Prot: ENSP00000499211.1 UniProt:
	CARD8 ENST00000391898.7	TSL:1	c.304T>C p.Phe102Leu	missense	Exon 3 of 11	Prot: ENSP00000375767.3 UniProt:
	CARD8 ENST00000520153.5	TSL:1	c.154T>C p.Phe52Leu	missense	Exon 4 of 12	Prot: ENSP00000428736.1 UniProt:

CARD8 ENST00000651546.1

MANE Select

HGVSc / HGVSpc.304T>Cp.Phe102Leu

Exon rankExon 6 of 14

missense

Prot: ENSP00000499211.1UniProt: Q9Y2G2-5

CARD8 ENST00000391898.7

TSL:1

HGVSc / HGVSpc.304T>Cp.Phe102Leu

Exon rankExon 3 of 11

missense

Prot: ENSP00000375767.3UniProt: Q9Y2G2-5

CARD8 ENST00000520153.5

TSL:1

HGVSc / HGVSpc.154T>Cp.Phe52Leu

Exon rankExon 4 of 12

missense

Prot: ENSP00000428736.1UniProt: Q9Y2G2-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 6.84e-7	AC:1	Hom:0	AN:1461556	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000131	1	76472	0.00	0	133188

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.095
DANN	Benign	0.32
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00046	N
FuncVEP CTI	Benign	0.0048
GPN-Star LLR	N/A	0.49
GPN-Star score	N/A	-0.49
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.00055	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	297/3	polymorphism
PhyloP100	Benign	-1.2
popEVE	Benign	-3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.40	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2043211;

hg19: chr19-48737706;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar