chr19-48234447-GAA-TAT

Variant names:

• chr19-48234447-GAA-TAT
• NM_001184900.3:c.304_306delTTCinsATA
• CARD8 p.Phe102Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001351784.2(CARD8):c.30_32delTTCinsATA (p.CysSer10*) variant causes a stop gained change. Note: NM_001351784.2 is not a MANE Select or MANE Plus Clinical transcript for CARD8; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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)
• Consequence: CARD8 NM_001351784.2 stop_gained
• 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 2 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.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001351784.2. 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.304_306delTTCinsATA p.Phe102Ile	missense	N/A	Prot: NP_001171829.1 UniProt:
	CARD8 NM_001351784.2		c.30_32delTTCinsATA p.CysSer10*	stop_gained	N/A	Prot: NP_001338713.1
	CARD8 NM_001365950.1		c.30_32delTTCinsATA p.CysSer10*	stop_gained	N/A	Prot: NP_001352879.1 UniProt:

CARD8 NM_001184900.3

MANE Select

HGVSc / HGVSpc.304_306delTTCinsATAp.Phe102Ile

Exon rankN/A

missense

Prot: NP_001171829.1UniProt: Q9Y2G2-5

CARD8 NM_001351784.2

HGVSc / HGVSpc.30_32delTTCinsATAp.CysSer10*

Exon rankN/A

stop_gained

Prot: NP_001338713.1

CARD8 NM_001365950.1

HGVSc / HGVSpc.30_32delTTCinsATAp.CysSer10*

Exon rankN/A

stop_gained

Prot: NP_001352879.1UniProt: Q9Y2G2-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CARD8 ENST00000651546.1	MANE Select	c.304_306delTTCinsATA p.Phe102Ile	missense	N/A	Prot: ENSP00000499211.1 UniProt:
	CARD8 ENST00000391898.7	TSL:1	c.304_306delTTCinsATA p.Phe102Ile	missense	N/A	Prot: ENSP00000375767.3 UniProt:
	CARD8 ENST00000520153.5	TSL:1	c.154_156delTTCinsATA p.Phe52Ile	missense	N/A	Prot: ENSP00000428736.1 UniProt:

CARD8 ENST00000651546.1

MANE Select

HGVSc / HGVSpc.304_306delTTCinsATAp.Phe102Ile

Exon rankN/A

missense

Prot: ENSP00000499211.1UniProt: Q9Y2G2-5

CARD8 ENST00000391898.7

TSL:1

HGVSc / HGVSpc.304_306delTTCinsATAp.Phe102Ile

Exon rankN/A

missense

Prot: ENSP00000375767.3UniProt: Q9Y2G2-5

CARD8 ENST00000520153.5

TSL:1

HGVSc / HGVSpc.154_156delTTCinsATAp.Phe52Ile

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.36

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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