1-111235744-C-G

Position:

• chr1-111235744-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004000.3(CHI3L2):​c.586C>G​(p.Gln196Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHI3L2 NM_004000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057480842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHI3L2	NM_004000.3	c.586C>G	p.Gln196Glu	missense_variant	6/11	ENST00000369748.9	NP_003991.2
CHI3L2	NM_001025197.1	c.556C>G	p.Gln186Glu	missense_variant	5/10		NP_001020368.1
CHI3L2	NM_001025199.2	c.349C>G	p.Gln117Glu	missense_variant	5/10		NP_001020370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHI3L2	ENST00000369748.9	c.586C>G	p.Gln196Glu	missense_variant	6/11	1	NM_004000.3	ENSP00000358763	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.586C>G (p.Q196E) alteration is located in exon 6 (coding exon 6) of the CHI3L2 gene. This alteration results from a C to G substitution at nucleotide position 586, causing the glutamine (Q) at amino acid position 196 to be replaced by a glutamic acid (E). 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	0.058
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.23
DEOGEN2	Benign	0.0052	T;.;T;.;T;T;.;.;.;T;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.66	.;T;T;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.057	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N;.;.;.;N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.049
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.015	B;.;.;.;B;.;.;.;.;.;.;.
Vest4		0.061
MutPred		0.49		Gain of disorder (P = 0.1485);Gain of disorder (P = 0.1485);Gain of disorder (P = 0.1485);.;Gain of disorder (P = 0.1485);.;.;.;.;.;.;.;
MVP		0.23
MPC		0.016
ClinPred		0.093	T
GERP RS		2.5
Varity_R		0.42
gMVP		0.29

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

Other links and lift over

dbSNP: rs1659865793; hg19: chr1-111778366;