19-48234449-A-C

Variant names:

• chr19-48234449-A-C
• rs2043211
• NM_001184900.3:c.304T>G
• CARD8 p.Phe102Val

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.304T>G (p.Phe102Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,556 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. 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.C10G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1399285)

• 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 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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD/XL gene (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.304T>G p.Phe102Val	missense	Exon 6 of 14	Prot: NP_001171829.1 UniProt:
	CARD8 NM_001351782.2		c.304T>G p.Phe102Val	missense	Exon 7 of 15	Prot: NP_001338711.1 UniProt:
	CARD8 NM_001184901.1		c.154T>G p.Phe52Val	missense	Exon 3 of 11	Prot: NP_001171830.1 UniProt:

CARD8 NM_001184900.3

MANE Select

HGVSc / HGVSpc.304T>Gp.Phe102Val

Exon rankExon 6 of 14

missense

Prot: NP_001171829.1UniProt: Q9Y2G2-5

CARD8 NM_001351782.2

HGVSc / HGVSpc.304T>Gp.Phe102Val

Exon rankExon 7 of 15

missense

Prot: NP_001338711.1UniProt: Q9Y2G2-5

CARD8 NM_001184901.1

HGVSc / HGVSpc.154T>Gp.Phe52Val

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>G p.Phe102Val	missense	Exon 6 of 14	Prot: ENSP00000499211.1 UniProt:
	CARD8 ENST00000391898.7	TSL:1	c.304T>G p.Phe102Val	missense	Exon 3 of 11	Prot: ENSP00000375767.3 UniProt:
	CARD8 ENST00000520153.5	TSL:1	c.154T>G p.Phe52Val	missense	Exon 4 of 12	Prot: ENSP00000428736.1 UniProt:

CARD8 ENST00000651546.1

MANE Select

HGVSc / HGVSpc.304T>Gp.Phe102Val

Exon rankExon 6 of 14

missense

Prot: ENSP00000499211.1UniProt: Q9Y2G2-5

CARD8 ENST00000391898.7

TSL:1

HGVSc / HGVSpc.304T>Gp.Phe102Val

Exon rankExon 3 of 11

missense

Prot: ENSP00000375767.3UniProt: Q9Y2G2-5

CARD8 ENST00000520153.5

TSL:1

HGVSc / HGVSpc.154T>Gp.Phe52Val

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: 6.84e-7	AC:1	Hom:0	AN:1461556	Cov:33
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	Benign	9.8
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.13
DANN	Benign	0.65
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0015	N
FuncVEP CTI	Benign	0.0031
GPN-Star LLR	N/A	0.44
GPN-Star score	N/A	-0.44
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.00071	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	297/3	polymorphism
PhyloP100	Benign	-1.2
popEVE	Benign	-3.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.046
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D

Showing 24 of 24 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

dbSNP: rs2043211;

hg19: chr19-48737706;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar