rs2043211

Variant names:

• chr19-48234449-A-T
• rs2043211
• NM_001184900.3:c.304T>A
• CARD8 p.Phe102Ile

Your query was ambiguous. Multiple possible variants found:

• chr19-48234449-A-T
• chr19-48234449-A-C
• chr19-48234449-A-G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP6_Strong

The NM_001351784.2(CARD8):c.30T>A (p.Cys10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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). The variant allele was found at a cumulative frequency of 0.323 (AC=520,684) in the gnomAD database across 1,612,308 control chromosomes, including 86,121 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.478. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7120 hom., cov: 32)
  • Exomes 𝑓: 0.33 (79001 hom.)
• Consequence: CARD8 NM_001351784.2 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23
• Publications: 255 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: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4776 — exceeds 5%% threshold (BA1 applied)

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.304T>A	p.Phe102Ile	missense	Exon 6 of 14	NP_001171829.1	Q9Y2G2-5
	CARD8	NM_001351784.2		c.30T>A	p.Cys10*	stop_gained	Exon 5 of 12	NP_001338713.1
	CARD8	NM_001365950.1		c.30T>A	p.Cys10*	stop_gained	Exon 4 of 11	NP_001352879.1	Q9Y2G2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD8	ENST00000651546.1	MANE Select	c.304T>A	p.Phe102Ile	missense	Exon 6 of 14	ENSP00000499211.1	Q9Y2G2-5
	CARD8	ENST00000391898.7	TSL:1	c.304T>A	p.Phe102Ile	missense	Exon 3 of 11	ENSP00000375767.3	Q9Y2G2-5
	CARD8	ENST00000520153.5	TSL:1	c.154T>A	p.Phe52Ile	missense	Exon 4 of 12	ENSP00000428736.1	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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.298	AC:45296	Hom:7119	AN:151914	Cov:32
GnomAD2 exomes	AF: 0.327	AC:82112	Hom:	AN:250934	Cov:
GnomAD4 exome	AF: 0.326	AC:475366	Hom:79001	AN:1460276	Cov:33
GnomAD4 genome	AF: 0.298	AC:45318	Hom:7120	AN:152032	Cov:32
TOPMed (Bravo)	AF: 0.288	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.320	AC:39110	Hom:6407	AN:122078	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.287	AC:671	Hom:96	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.495	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.343	AC:103	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.288	AC:3748	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.416	AC:1446	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.448	AC:3239	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.321	AC:645	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.384	AC:46991	Hom:9145	AN:122400	Cov:
Turkish Variome	AF: 0.320	AC:2147	Hom:357	AN:6714	Cov:
UK10K	AF: 0.313	AC:2367	Hom:	AN:7562	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.325 *	3534	10878	0.328 *	5697	17386
BipEx(Bipolar disorder (including schizoaffective))	0.330	9383	28412	0.329	9499	28832
Epi25(Epilepsy)	0.334	14003	41944	0.315	21042	66860
SCHEMA(Schizophrenia)	0.366	56232	153672	0.358	88518	247164

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.15
DANN	Benign	0.86
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0018	N
FuncVEP CTI	Benign	0.0028
GPN-Star LLR	N/A	0.30
GPN-Star score	N/A	-0.30
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.93	T
Mutation Taster	N/A	170/30	polymorphism (auto)
PhyloP100	Benign	-1.2
popEVE	Benign	-3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.070	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.025
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D

Showing 25 of 25 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.

Other links and lift over

dbSNP: rs2043211;

hg19: chr19-48737706;

COSMIC: COSV62872790;

COSMIC: COSV62872790;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar