chr19-48211939-T-C

Position:

• chr19-48211939-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184900.3(CARD8):​c.1385A>G​(p.Gln462Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,614,094 control chromosomes in the GnomAD database, including 547 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (26 hom., cov: 32)
  • Exomes 𝑓: 0.024 (521 hom.)
• Consequence: CARD8 NM_001184900.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.216

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]

ENSG00000268583 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034770072).
• BP6: Variant 19-48211939-T-C is Benign according to our data. Variant chr19-48211939-T-C is described in ClinVar as [Benign]. Clinvar id is 1169236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48211939-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0181 (2763/152278) while in subpopulation NFE AF= 0.0282 (1917/68018). AF 95% confidence interval is 0.0271. There are 26 homozygotes in gnomad4. There are 1326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2763 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD8	NM_001184900.3	c.1385A>G	p.Gln462Arg	missense_variant	14/14	ENST00000651546.1	NP_001171829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD8	ENST00000651546.1	c.1385A>G	p.Gln462Arg	missense_variant	14/14		NM_001184900.3	ENSP00000499211.1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2763 AN: 152160 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0198 AC: 4962 AN: 250060 Hom.: 76 AF XY: 0.0198 AC XY: 2672 AN XY: 135266

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0384

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0243 AC: 35483 AN: 1461816 Hom.: 521 Cov.: 36 AF XY: 0.0236 AC XY: 17140 AN XY: 727212

Gnomad4 AFR exome AF: 0.00376

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0396

Gnomad4 NFE exome AF: 0.0280

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0181 AC: 2763 AN: 152278 Hom.: 26 Cov.: 32 AF XY: 0.0178 AC XY: 1326 AN XY: 74452

Gnomad4 AFR AF: 0.00448

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.0282

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0232 Hom.: 27

Bravo AF: 0.0162

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0252 AC: 217

ExAC AF: 0.0204 AC: 2482

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0254

EpiControl AF: 0.0248

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.8
DANN	Uncertain	0.99
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.52	T;T;.;.;.
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.037	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.090
MPC		0.20
ClinPred		0.0093	T
GERP RS		-0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34632751; hg19: chr19-48715196;