11-74703481-T-C

Variant names:

• chr11-74703481-T-C
• rs767286688
• NM_001278473.3:c.770A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001278473.3(CHRDL2):​c.770A>G​(p.Lys257Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,451,458 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHRDL2 NM_001278473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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]

ACMG classification

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=0.2987122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRDL2	NM_001278473.3	c.770A>G	p.Lys257Arg	missense_variant	Exon 8 of 11	ENST00000376332.8	NP_001265402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRDL2	ENST00000376332.8	c.770A>G	p.Lys257Arg	missense_variant	Exon 8 of 11	1	NM_001278473.3	ENSP00000365510.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000846 AC: 2 AN: 236364 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128212

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1451458 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 721006

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: 0.00000543

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.770A>G (p.K257R) alteration is located in exon 8 (coding exon 8) of the CHRDL2 gene. This alteration results from a A to G substitution at nucleotide position 770, causing the lysine (K) at amino acid position 257 to be replaced by an arginine (R). 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	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;.
Eigen	Benign	0.044
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.40	N;N;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.85	N;N;.
REVEL	Benign	0.089
Sift	Benign	0.030	D;D;.
Sift4G	Benign	0.19	T;T;T
Polyphen		0.12	B;B;.
Vest4		0.32
MutPred		0.54		Loss of ubiquitination at K257 (P = 0.0362);Loss of ubiquitination at K257 (P = 0.0362);.;
MVP		0.86
MPC		0.22
ClinPred		0.27	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.40

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

Other links and lift over

dbSNP: rs767286688; hg19: chr11-74414526;