Genetic Variant CLEC18A:p.Pro94Leu (chr16-69954398-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001370523.4(CLEC18A):c.281C>T(p.Pro94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000599 in 150,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLEC18A
NM_001370523.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.952

Variant links:

Genes affected

CLEC18A (HGNC:30388): (C-type lectin domain family 18 member A) This is one of three closely related paralogous genes on chromosome 16 encoding secreted proteins containing C-type lectin domains. These domains bind to carbohydrates in the presence of calcium, and may be involved in cell adhesion, immune response and apoptosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2012]

CLEC18A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10248837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC18A	NM_001370523.4 link	c.281C>T	p.Pro94Leu	missense_variant	Exon 3 of 12	ENST00000288040.11	NP_001357452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC18A	ENST00000288040.11 link	c.281C>T	p.Pro94Leu	missense_variant	Exon 3 of 12	1	NM_001370523.4	ENSP00000288040.6		A5D8T8-1

Frequencies

GnomAD3 genomes

AF:

0.0000599

AC:

AN:

150214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000668

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:

0.000104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248604

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134562

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000137

AC:

200

AN:

1459908

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

726320

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000599

AC:

AN:

150214

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73160

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000668

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281C>T (p.P94L) alteration is located in exon 4 (coding exon 3) of the CLEC18A gene. This alteration results from a C to T substitution at nucleotide position 281, causing the proline (P) at amino acid position 94 to be replaced by a leucine (L). 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

0.074

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.0

DANN

Benign

0.71

DEOGEN2

Benign

0.0071

T;T;T;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.65

T;.;.;.;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;M;M;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

.;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.16

.;T;T;T;T

Sift4G

Benign

0.27

T;T;T;T;T

Polyphen

0.037

B;B;B;B;B

Vest4

0.20

MutPred

0.41

Loss of glycosylation at P94 (P = 0.027);Loss of glycosylation at P94 (P = 0.027);Loss of glycosylation at P94 (P = 0.027);Loss of glycosylation at P94 (P = 0.027);Loss of glycosylation at P94 (P = 0.027);

MVP

0.27

MPC

0.50

ClinPred

0.025

GERP RS

0.95

Varity_R

0.032

gMVP

0.22

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