chr11-74702919-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001278473.3(CHRDL2):​c.995C>T​(p.Pro332Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,842 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: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CHRDL2
NM_001278473.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12
Variant links:
Genes affected
CHRDL2 (HGNC:24168): (chordin like 2) This gene encodes a member of the chordin family of proteins. Chordin family members are secreted proteins that share a cysteine-rich pro-collagen repeat domain and associate with members of the transforming growth factor beta superfamily. In vitro assays demonstrate a direct interaction between the encoded protein and human activin A. This gene is expressed in many tissues including osteoblasts, where it is differentially expressed during differentiation. In addition, its expression is upregulated in human osteoarthritic joint cartilage, suggesting a role in adult cartilage regeneration. [provided by RefSeq, Jan 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2884449).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRDL2NM_001278473.3 linkc.995C>T p.Pro332Leu missense_variant Exon 9 of 11 ENST00000376332.8 NP_001265402.1 Q6WN34-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRDL2ENST00000376332.8 linkc.995C>T p.Pro332Leu missense_variant Exon 9 of 11 1 NM_001278473.3 ENSP00000365510.3 Q6WN34-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461842
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727226
show subpopulations
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
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
Jun 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.995C>T (p.P332L) alteration is located in exon 9 (coding exon 9) of the CHRDL2 gene. This alteration results from a C to T substitution at nucleotide position 995, causing the proline (P) at amino acid position 332 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
Benign
0.092
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
.;T;.;T
Eigen
Benign
0.12
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.29
T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.1
M;M;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.9
N;N;.;N
REVEL
Benign
0.20
Sift
Benign
0.75
T;T;.;D
Sift4G
Benign
0.13
T;T;T;.
Polyphen
0.99
D;B;.;.
Vest4
0.43
MutPred
0.34
Loss of ubiquitination at K333 (P = 0.0421);Loss of ubiquitination at K333 (P = 0.0421);.;.;
MVP
0.88
MPC
0.81
ClinPred
0.85
D
GERP RS
3.9
Varity_R
0.072
gMVP
0.61

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2033876169; hg19: chr11-74413964; API