chr1-111235755-A-C

Variant names:

• chr1-111235755-A-C
• NM_004000.3:c.597A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004000.3(CHI3L2):​c.597A>C​(p.Lys199Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHI3L2 NM_004000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0570
• Publications: 0 publications found

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

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=0.14641339).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHI3L2	NM_004000.3	c.597A>C	p.Lys199Asn	missense_variant	Exon 6 of 11	ENST00000369748.9	NP_003991.2
CHI3L2	NM_001025197.1	c.567A>C	p.Lys189Asn	missense_variant	Exon 5 of 10		NP_001020368.1
CHI3L2	NM_001025199.2	c.360A>C	p.Lys120Asn	missense_variant	Exon 5 of 10		NP_001020370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHI3L2	ENST00000369748.9	c.597A>C	p.Lys199Asn	missense_variant	Exon 6 of 11	1	NM_004000.3	ENSP00000358763.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461376 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.597A>C (p.K199N) alteration is located in exon 6 (coding exon 6) of the CHI3L2 gene. This alteration results from a A to C substitution at nucleotide position 597, causing the lysine (K) at amino acid position 199 to be replaced by an asparagine (N). 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	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;.;T;.;T;T;.;.;.;T;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	.;T;T;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	M;.;.;.;M;.;.;.;.;.;.;.
PhyloP100		0.057
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N;N;N;D;N;N;N;D;D;D;N;N
REVEL	Benign	0.026
Sift	Benign	0.042	D;D;D;T;D;T;T;T;D;T;T;D
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.87	P;.;.;.;P;.;.;.;.;.;.;.
Vest4		0.085
MutPred		0.50		Loss of methylation at K199 (P = 0.0438);Loss of methylation at K199 (P = 0.0438);Loss of methylation at K199 (P = 0.0438);.;Loss of methylation at K199 (P = 0.0438);.;.;.;.;.;.;.;
MVP		0.24
MPC		0.016
ClinPred		0.15	T
GERP RS		2.3
Varity_R		0.55
gMVP		0.32
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

hg19: chr1-111778377;