11-74704554-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278473.3(CHRDL2):​c.683G>A​(p.Arg228His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,580,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CHRDL2
NM_001278473.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.844
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14081708).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRDL2NM_001278473.3 linkc.683G>A p.Arg228His missense_variant Exon 7 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.683G>A p.Arg228His missense_variant Exon 7 of 11 1 NM_001278473.3 ENSP00000365510.3 Q6WN34-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000452
AC:
10
AN:
221184
Hom.:
0
AF XY:
0.0000582
AC XY:
7
AN XY:
120204
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000197
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000476
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000399
AC:
57
AN:
1428438
Hom.:
0
Cov.:
31
AF XY:
0.0000494
AC XY:
35
AN XY:
709192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.000300
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000374
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000346
Gnomad4 OTH exome
AF:
0.0000339
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.683G>A (p.R228H) alteration is located in exon 7 (coding exon 7) of the CHRDL2 gene. This alteration results from a G to A substitution at nucleotide position 683, causing the arginine (R) at amino acid position 228 to be replaced by a histidine (H). 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
0.073
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.036
.;T;.;T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.044
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.89
D;D;D;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.14
T;T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.9
L;L;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.6
N;N;.;N
REVEL
Benign
0.060
Sift
Uncertain
0.015
D;D;.;D
Sift4G
Uncertain
0.026
D;D;D;.
Polyphen
0.27
B;B;.;.
Vest4
0.28
MutPred
0.36
Loss of MoRF binding (P = 0.0175);Loss of MoRF binding (P = 0.0175);.;Loss of MoRF binding (P = 0.0175);
MVP
0.78
MPC
0.32
ClinPred
0.14
T
GERP RS
3.4
Varity_R
0.097
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs766056484; hg19: chr11-74415599; COSMIC: COSV55222562; COSMIC: COSV55222562; API