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GeneBe

19-48211908-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001184900.3(CARD8):c.1416C>T(p.Leu472=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,896 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 39 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 33 hom. )

Consequence

CARD8
NM_001184900.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.695
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-48211908-G-A is Benign according to our data. Variant chr19-48211908-G-A is described in ClinVar as [Benign]. Clinvar id is 782653.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.695 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1758/152090) while in subpopulation AFR AF= 0.0384 (1592/41462). AF 95% confidence interval is 0.0368. There are 39 homozygotes in gnomad4. There are 821 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1756 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CARD8NM_001184900.3 linkuse as main transcriptc.1416C>T p.Leu472= synonymous_variant 14/14 ENST00000651546.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CARD8ENST00000651546.1 linkuse as main transcriptc.1416C>T p.Leu472= synonymous_variant 14/14 NM_001184900.3 A2Q9Y2G2-5
ENST00000595201.2 linkuse as main transcriptn.390-1058G>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0116
AC:
1756
AN:
151972
Hom.:
39
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0385
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00741
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00862
GnomAD3 exomes
AF:
0.00299
AC:
751
AN:
250884
Hom.:
17
AF XY:
0.00207
AC XY:
281
AN XY:
135650
show subpopulations
Gnomad AFR exome
AF:
0.0383
Gnomad AMR exome
AF:
0.00197
Gnomad ASJ exome
AF:
0.00268
Gnomad EAS exome
AF:
0.000381
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00123
AC:
1799
AN:
1461806
Hom.:
33
Cov.:
36
AF XY:
0.00107
AC XY:
780
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0370
Gnomad4 AMR exome
AF:
0.00246
Gnomad4 ASJ exome
AF:
0.00268
Gnomad4 EAS exome
AF:
0.000227
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000153
Gnomad4 OTH exome
AF:
0.00300
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0116
AC:
1758
AN:
152090
Hom.:
39
Cov.:
32
AF XY:
0.0110
AC XY:
821
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0384
Gnomad4 AMR
AF:
0.00740
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.000580
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00853
Alfa
AF:
0.00630
Hom.:
20
Bravo
AF:
0.0137
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000415

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
Cadd
Benign
1.7
Dann
Benign
0.66

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61755273; hg19: chr19-48715165; API