Genetic Variant CHI3L2:p.Pro93Ala (chr1-111231242-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004000.3(CHI3L2):c.277C>G(p.Pro93Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P93T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CHI3L2
NM_004000.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.542

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16925842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHI3L2	NM_004000.3 link	c.277C>G	p.Pro93Ala	missense_variant	Exon 4 of 11	ENST00000369748.9	NP_003991.2	Q15782-4
CHI3L2	NM_001025197.1 link	c.247C>G	p.Pro83Ala	missense_variant	Exon 3 of 10		NP_001020368.1	Q15782-6
CHI3L2	NM_001025199.2 link	c.40C>G	p.Pro14Ala	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.277C>G	p.Pro93Ala	missense_variant	Exon 4 of 11	1	NM_004000.3	ENSP00000358763.4		Q15782-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250988

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725354

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1108028

Other (OTH)

AF:

0.00

AC:

AN:

60246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.084

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.91

.;D;D;T;T;D;.;T;D;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

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

PhyloP100

0.54

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.8

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

REVEL

Benign

0.093

Sift

Benign

0.038

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

Sift4G

Uncertain

0.051

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

Polyphen

0.019

B;.;.;.;B;.;.;.;.;.

Vest4

0.24

MutPred

0.59

Loss of glycosylation at P93 (P = 0.0118);Loss of glycosylation at P93 (P = 0.0118);Loss of glycosylation at P93 (P = 0.0118);.;Loss of glycosylation at P93 (P = 0.0118);Loss of glycosylation at P93 (P = 0.0118);.;.;.;.;

MVP

0.48

MPC

0.017

ClinPred

0.42

GERP RS

2.7

PromoterAI

0.018

Neutral

(source)

Varity_R

0.31

gMVP

0.39

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over