Genetic Variant CLEC18B:p.Cys147Arg (chr16-74418076-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001385193.1(CLEC18B):c.439T>C(p.Cys147Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLEC18B
NM_001385193.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.87

Variant links:

Genes affected

CLEC18B (HGNC:33849): (C-type lectin domain family 18 member B) Predicted to enable polysaccharide binding activity. Predicted to be located in Golgi apparatus; endosome; and sarcoplasmic reticulum. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

CLEC18B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC18B	NM_001385193.1 link	c.439T>C	p.Cys147Arg	missense_variant	Exon 3 of 12	ENST00000682950.1	NP_001372122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLEC18B	ENST00000682950.1 link	c.439T>C	p.Cys147Arg	missense_variant	Exon 3 of 12		NM_001385193.1	ENSP00000507367.1	A0A804HJ60
CLEC18B	ENST00000339953.9 link	c.439T>C	p.Cys147Arg	missense_variant	Exon 3 of 13	1		ENSP00000341051.5	Q6UXF7-1
CLEC18B	ENST00000425714.2 link	n.416+2425T>C		intron_variant	Intron 2 of 6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000519

AC:

AN:

192754

Hom.:

AF XY:

0.00000953

AC XY:

AN XY:

104986

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:

0.0000393

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000111

AC:

AN:

1442696

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

717168

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:

0.0000357

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.439T>C (p.C147R) alteration is located in exon 3 (coding exon 3) of the CLEC18B gene. This alteration results from a T to C substitution at nucleotide position 439, causing the cysteine (C) at amino acid position 147 to be replaced by an arginine (R). 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

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;.;T;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;.;T;T

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

4.3

.;.;H;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-10

.;.;D;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.96

.;.;D;.

Vest4

0.94

MutPred

0.77

Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);

MVP

0.15

ClinPred

1.0

GERP RS

3.6

Varity_R

0.94

gMVP

0.95

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