Genetic Variant CHI3L2:p.Phe106Leu (chr1-111231281-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004000.3(CHI3L2):c.316T>C(p.Phe106Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,610,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

CHI3L2
NM_004000.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05092323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHI3L2	NM_004000.3 link	c.316T>C	p.Phe106Leu	missense_variant	Exon 4 of 11	ENST00000369748.9	NP_003991.2	Q15782-4
CHI3L2	NM_001025197.1 link	c.286T>C	p.Phe96Leu	missense_variant	Exon 3 of 10		NP_001020368.1	Q15782-6
CHI3L2	NM_001025199.2 link	c.79T>C	p.Phe27Leu	missense_variant	Exon 3 of 10		NP_001020370.1	Q15782-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHI3L2	ENST00000369748.9 link	c.316T>C	p.Phe106Leu	missense_variant	Exon 4 of 11	1	NM_004000.3	ENSP00000358763.4		Q15782-4

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000997

AC:

AN:

250808

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1458180

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725682

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1108908

Other (OTH)

AF:

0.0000664

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000440

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41582

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000476

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.316T>C (p.F106L) alteration is located in exon 4 (coding exon 4) of the CHI3L2 gene. This alteration results from a T to C substitution at nucleotide position 316, causing the phenylalanine (F) at amino acid position 106 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

Pathogenic

0.73

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

T;.;T;.;T;T;.;.;T;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.031

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.69

.;T;T;T;T;T;.;T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.051

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.;.;M;.;.;.;.;.

PhyloP100

3.0

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.9

D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.019

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;D;D;T;T;T;D;T

Polyphen

0.98

D;.;.;.;D;.;.;.;.;.

Vest4

0.40

MutPred

0.64

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;.;.;.;

MVP

0.24

MPC

0.030

ClinPred

0.17

GERP RS

2.8

Varity_R

0.71

gMVP

0.39

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-111231281-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over