1-111236125-A-C

Variant names:

• chr1-111236125-A-C
• rs753494309
• NM_004000.3:c.707A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004000.3(CHI3L2):​c.707A>C​(p.Asp236Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CHI3L2 NM_004000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHI3L2	NM_004000.3	c.707A>C	p.Asp236Ala	missense_variant	Exon 7 of 11	ENST00000369748.9	NP_003991.2
CHI3L2	NM_001025197.1	c.677A>C	p.Asp226Ala	missense_variant	Exon 6 of 10		NP_001020368.1
CHI3L2	NM_001025199.2	c.470A>C	p.Asp157Ala	missense_variant	Exon 6 of 10		NP_001020370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHI3L2	ENST00000369748.9	c.707A>C	p.Asp236Ala	missense_variant	Exon 7 of 11	1	NM_004000.3	ENSP00000358763.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727244

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: 0.0000252

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.707A>C (p.D236A) alteration is located in exon 7 (coding exon 7) of the CHI3L2 gene. This alteration results from a A to C substitution at nucleotide position 707, causing the aspartic acid (D) at amino acid position 236 to be replaced by an alanine (A). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.;T;.;.;.;.;T
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	.;T;T;.;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.040	D;D;D;T;D;D;T;T
Sift4G	Uncertain	0.056	T;T;T;T;D;D;T;T
Polyphen		0.96	D;.;D;.;.;.;.;.
Vest4		0.55
MutPred		0.71		Loss of disorder (P = 0.0885);.;Loss of disorder (P = 0.0885);.;.;.;.;.;
MVP		0.40
MPC		0.10
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.48
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753494309; hg19: chr1-111778747;