rs2298258

chr1-162767326-C-Gchr1-162767326-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006182.4(DDR2):c.1260C>G(p.Leu420=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,613,736 control chromosomes in the GnomAD database, including 35,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L420L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (6952 hom., cov: 32)
  • Exomes 𝑓: 0.18 (28817 hom.)
• Consequence: DDR2 NM_006182.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.244

Genes affected

DDR2 (HGNC:2731): (discoidin domain receptor tyrosine kinase 2) This gene encodes a member of the discoidin domain receptor subclass of the receptor tyrosine kinase (RTKs) protein family. RTKs play a key role in the communication of cells with their microenvironment. The encoded protein is a collagen-induced receptor that activates signal transduction pathways involved in cell adhesion, proliferation, and extracellular matrix remodeling. This protein is expressed in numerous cell types and may alos be involved in wound repair and regulate tumor growth and invasiveness. Mutations in this gene are the cause of short limb-hand type spondylometaepiphyseal dysplasia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 1-162767326-C-G is Benign according to our data. Variant chr1-162767326-C-G is described in ClinVar as [Benign]. Clinvar id is 259929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.244 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDR2	NM_006182.4	c.1260C>G	p.Leu420=	synonymous_variant	11/18	ENST00000367921.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDR2	ENST00000367921.8	c.1260C>G	p.Leu420=	synonymous_variant	11/18	1	NM_006182.4	P1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39484 AN: 151906 Hom.: 6925 Cov.: 32

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.0742

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.227 AC: 56989 AN: 251200 Hom.: 8770 AF XY: 0.214 AC XY: 29030 AN XY: 135758

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.397

Gnomad SAS exome AF: 0.268

Gnomad FIN exome AF: 0.0744

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.177 AC: 259400 AN: 1461712 Hom.: 28817 Cov.: 33 AF XY: 0.177 AC XY: 128611 AN XY: 727160

Gnomad4 AFR exome AF: 0.488

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.0813

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.260 AC: 39558 AN: 152024 Hom.: 6952 Cov.: 32 AF XY: 0.261 AC XY: 19376 AN XY: 74328

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.0994

Gnomad4 EAS AF: 0.412

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.0742

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.237

Alfa AF: 0.170 Hom.: 968

Bravo AF: 0.291

Asia WGS AF: 0.383 AC: 1327 AN: 3478

EpiCase AF: 0.139

EpiControl AF: 0.141

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Warburg-cinotti syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Squamous cell lung carcinoma Benign:1

Likely benign, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	6.1
Dann	Benign	0.76

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

Other links and lift over

dbSNP: rs2298258; hg19: chr1-162737116; COSMIC: COSV63369342;