11-74703379-C-T

Variant names:

• chr11-74703379-C-T
• rs200003845
• NM_001278473.3:c.872G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001278473.3(CHRDL2):​c.872G>A​(p.Arg291His) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,613,706 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 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CHRDL2 NM_001278473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13438237).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278473.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRDL2	NM_001278473.3	MANE Select	c.872G>A	p.Arg291His	missense	Exon 8 of 11	NP_001265402.1	Q6WN34-1
	CHRDL2	NM_015424.6		c.872G>A	p.Arg291His	missense	Exon 8 of 12	NP_056239.3
	CHRDL2	NM_001304390.2		c.812G>A	p.Arg271His	missense	Exon 7 of 11	NP_001291319.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRDL2	ENST00000376332.8	TSL:1 MANE Select	c.872G>A	p.Arg291His	missense	Exon 8 of 11	ENSP00000365510.3	Q6WN34-1
	CHRDL2	ENST00000263671.9	TSL:1	c.872G>A	p.Arg291His	missense	Exon 8 of 12	ENSP00000263671.5	Q6WN34-2
	CHRDL2	ENST00000528789.1	TSL:1	c.752-412G>A		intron	N/A	ENSP00000431380.1	Q6WN33

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250876 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461384 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727040

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111900

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74492

African (AFR) AF: 0.000240 AC: 10 AN: 41592

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000490 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.33
Sift	Benign	0.094	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.20	B
Vest4		0.36
MVP		0.89
MPC		0.32
ClinPred		0.13	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.46
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs200003845; hg19: chr11-74414424; COSMIC: COSV55225641; COSMIC: COSV55225641;