chr19-48211775-G-C

Variant names:

• chr19-48211775-G-C
• rs35920934
• NM_001184900.3:c.1549C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001184900.3(CARD8):​c.1549C>G​(p.Leu517Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.457
• Publications: 1 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)

ENSG00000268583 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072036684).
• BP6: Variant 19-48211775-G-C is Benign according to our data. Variant chr19-48211775-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1116126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD8	NM_001184900.3	MANE Select	c.1549C>G	p.Leu517Val	missense	Exon 14 of 14	NP_001171829.1	Q9Y2G2-5
	CARD8	NM_001351782.2		c.1549C>G	p.Leu517Val	missense	Exon 15 of 15	NP_001338711.1	Q9Y2G2-5
	CARD8	NM_001184901.1		c.1399C>G	p.Leu467Val	missense	Exon 11 of 11	NP_001171830.1	Q9Y2G2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD8	ENST00000651546.1	MANE Select	c.1549C>G	p.Leu517Val	missense	Exon 14 of 14	ENSP00000499211.1	Q9Y2G2-5
	CARD8	ENST00000391898.7	TSL:1	c.1549C>G	p.Leu517Val	missense	Exon 11 of 11	ENSP00000375767.3	Q9Y2G2-5
	CARD8	ENST00000520153.5	TSL:1	c.1399C>G	p.Leu467Val	missense	Exon 12 of 12	ENSP00000428736.1	Q9Y2G2-4

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000342 AC: 86 AN: 251428 AF XY: 0.000265

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.000105 AC XY: 76 AN XY: 727238

African (AFR) AF: 0.00556 AC: 186 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.000248 AC: 15 AN: 60396

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74458

African (AFR) AF: 0.00448 AC: 186 AN: 41550

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.00154

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.4
DANN	Benign	0.96
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.46
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Vest4		0.29
MVP		0.10
MPC		0.59
ClinPred		0.019	T
GERP RS		-1.6
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35920934; hg19: chr19-48715032;