Variant 1-111238768-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004000.3(CHI3L2):c.754T>C(p.Trp252Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000055 ( 0 hom. )

Consequence

CHI3L2
NM_004000.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.41

Variant links:

Genes affected

CHI3L2 (HGNC:1933): (chitinase 3 like 2) The protein encoded by this gene is similar to bacterial chitinases but lacks chitinase activity. The encoded protein is secreted and is involved in cartilage biogenesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CHI3L2 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, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHI3L2	NM_004000.3 linkuse as main transcript	c.754T>C	p.Trp252Arg	missense_variant	8/11	ENST00000369748.9	NP_003991.2
CHI3L2	NM_001025197.1 linkuse as main transcript	c.724T>C	p.Trp242Arg	missense_variant	7/10		NP_001020368.1
CHI3L2	NM_001025199.2 linkuse as main transcript	c.517T>C	p.Trp173Arg	missense_variant	7/10		NP_001020370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHI3L2	ENST00000369748.9 linkuse as main transcript	c.754T>C	p.Trp252Arg	missense_variant	8/11	1	NM_004000.3	ENSP00000358763	P1	Q15782-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727142

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

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

Oct 25, 2022

The c.754T>C (p.W252R) alteration is located in exon 8 (coding exon 8) of the CHI3L2 gene. This alteration results from a T to C substitution at nucleotide position 754, causing the tryptophan (W) at amino acid position 252 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

0.96

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.;T;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.30

.;T;T;.;T

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

3.9

H;.;H;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-10

D;D;D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.89

MutPred

0.82

Gain of methylation at W252 (P = 0.0197);.;Gain of methylation at W252 (P = 0.0197);.;.;

MVP

0.30

MPC

0.13

ClinPred

1.0

GERP RS

3.4

Varity_R

0.98

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over