Variant 11-105138860-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_021571.4(CARD18):c.226C>T(p.Leu76Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CARD18
NM_021571.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.23

Variant links:

Genes affected

CARD18 (HGNC:28861): (caspase recruitment domain family member 18) Enables CARD domain binding activity and caspase binding activity. Involved in inhibition of cysteine-type endopeptidase activity; negative regulation of interleukin-1 beta production; and negative regulation of protein binding activity. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

CARD18 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD18	NM_021571.4 linkuse as main transcript	c.226C>T	p.Leu76Phe	missense_variant	2/3	ENST00000530950.2	NP_067546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CARD18	ENST00000530950.2 linkuse as main transcript	c.226C>T	p.Leu76Phe	missense_variant	2/3	5	NM_021571.4	ENSP00000436691	P1
CARD18	ENST00000526823.1 linkuse as main transcript	c.109C>T	p.Leu37Phe	missense_variant	1/2	1		ENSP00000437035
CARD18	ENST00000532895.1 linkuse as main transcript	c.109C>T	p.Leu37Phe	missense_variant	2/3	2		ENSP00000437187
CARD18	ENST00000649856.1 linkuse as main transcript	c.109C>T	p.Leu37Phe	missense_variant	7/8			ENSP00000497940

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248934

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135042

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461372

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.226C>T (p.L76F) alteration is located in exon 2 (coding exon 2) of the CARD18 gene. This alteration results from a C to T substitution at nucleotide position 226, causing the leucine (L) at amino acid position 76 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.5

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

T;.;.;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.64

T;.;.;T

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.2

N;.;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0030

D;.;D;D

Sift4G

Uncertain

0.035

D;.;D;D

Polyphen

0.97

D;.;.;.

Vest4

0.30

MutPred

0.76

Gain of ubiquitination at K74 (P = 0.0754);.;.;.;

MVP

0.081

MPC

0.23

ClinPred

0.91

GERP RS

-5.4

Varity_R

0.11

gMVP

0.21

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over