11-74702845-C-T

Variant summary

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

The NM_001278473.3(CHRDL2):​c.1069G>A​(p.Glu357Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,614,114 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CHRDL2
NM_001278473.3 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35568398).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRDL2NM_001278473.3 linkc.1069G>A p.Glu357Lys 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.1069G>A p.Glu357Lys missense_variant Exon 9 of 11 1 NM_001278473.3 ENSP00000365510.3 Q6WN34-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251472
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461872
Hom.:
0
Cov.:
33
AF XY:
0.0000330
AC XY:
24
AN XY:
727240
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:
0.000290
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000494
AC:
6

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 07, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1069G>A (p.E357K) alteration is located in exon 9 (coding exon 9) of the CHRDL2 gene. This alteration results from a G to A substitution at nucleotide position 1069, causing the glutamic acid (E) at amino acid position 357 to be replaced by a lysine (K). 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
0.36
BayesDel_addAF
Benign
-0.062
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.045
.;T;.;T
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.36
T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.2
M;M;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-2.1
N;N;.;N
REVEL
Uncertain
0.30
Sift
Uncertain
0.0020
D;D;.;D
Sift4G
Uncertain
0.013
D;D;D;.
Polyphen
1.0
D;D;.;.
Vest4
0.67
MutPred
0.64
Gain of ubiquitination at E357 (P = 0.0131);Gain of ubiquitination at E357 (P = 0.0131);.;.;
MVP
0.85
MPC
0.92
ClinPred
0.44
T
GERP RS
5.1
Varity_R
0.51
gMVP
0.81

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: rs560101651; hg19: chr11-74413890; COSMIC: COSV55222636; COSMIC: COSV55222636; API