19-48234447-G-T

Variant names:

• chr19-48234447-G-T
• NM_001184900.3:c.306C>A
• CARD8 p.Phe102Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_001184900.3(CARD8):c.306C>A (p.Phe102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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); p.S11= (synonymous): Uncertain_significance (ClinVar VariationId 1423300, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.357
• Publications: 0 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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.306C>A p.Phe102Leu	missense	Exon 6 of 14	Prot: NP_001171829.1 UniProt:
	CARD8 NM_001351782.2		c.306C>A p.Phe102Leu	missense	Exon 7 of 15	Prot: NP_001338711.1 UniProt:
	CARD8 NM_001184901.1		c.156C>A p.Phe52Leu	missense	Exon 3 of 11	Prot: NP_001171830.1 UniProt:

CARD8 NM_001184900.3

MANE Select

HGVSc / HGVSpc.306C>Ap.Phe102Leu

Exon rankExon 6 of 14

missense

Prot: NP_001171829.1UniProt: Q9Y2G2-5

CARD8 NM_001351782.2

HGVSc / HGVSpc.306C>Ap.Phe102Leu

Exon rankExon 7 of 15

missense

Prot: NP_001338711.1UniProt: Q9Y2G2-5

CARD8 NM_001184901.1

HGVSc / HGVSpc.156C>Ap.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.306C>A p.Phe102Leu	missense	Exon 6 of 14	Prot: ENSP00000499211.1 UniProt:
	CARD8 ENST00000391898.7	TSL:1	c.306C>A p.Phe102Leu	missense	Exon 3 of 11	Prot: ENSP00000375767.3 UniProt:
	CARD8 ENST00000520153.5	TSL:1	c.156C>A p.Phe52Leu	missense	Exon 4 of 12	Prot: ENSP00000428736.1 UniProt:

CARD8 ENST00000651546.1

MANE Select

HGVSc / HGVSpc.306C>Ap.Phe102Leu

Exon rankExon 6 of 14

missense

Prot: ENSP00000499211.1UniProt: Q9Y2G2-5

CARD8 ENST00000391898.7

TSL:1

HGVSc / HGVSpc.306C>Ap.Phe102Leu

Exon rankExon 3 of 11

missense

Prot: ENSP00000375767.3UniProt: Q9Y2G2-5

CARD8 ENST00000520153.5

TSL:1

HGVSc / HGVSpc.156C>Ap.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	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.2
DANN	Benign	0.53
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
FuncVEP CTI	Benign	0.0035
GPN-Star LLR	N/A	0.32
GPN-Star score	N/A	-0.32
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.99	T
Mutation Taster	N/A	97/3	polymorphism
PhyloP100	Benign	0.36
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	0.011
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	0.010
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

hg19: chr19-48737704;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar