rs56351141

Positions:

chr1-162759823-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_006182.4(DDR2):c.699C>T(p.Thr233Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,614,036 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0092 ( 10 hom., cov: 32)

Exomes 𝑓: 0.013 ( 165 hom. )

Consequence

DDR2
NM_006182.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -1.56

Variant links:

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]

DDR2 links:

DDR2 (HGNC:):

DDR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 1-162759823-C-T is Benign according to our data. Variant chr1-162759823-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259935.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}.

BP7

Synonymous conserved (PhyloP=-1.56 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00924 (1407/152216) while in subpopulation AMR AF= 0.0145 (221/15290). AF 95% confidence interval is 0.0132. There are 10 homozygotes in gnomad4. There are 671 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDR2	NM_006182.4 linkuse as main transcript	c.699C>T	p.Thr233Thr	synonymous_variant	8/18	ENST00000367921.8	NP_006173.2	Q16832A0A024R906

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DDR2	ENST00000367921.8 linkuse as main transcript	c.699C>T	p.Thr233Thr	synonymous_variant	8/18	1	NM_006182.4	ENSP00000356898.3	Q16832
DDR2	ENST00000367922.7 linkuse as main transcript	c.699C>T	p.Thr233Thr	synonymous_variant	9/19	1		ENSP00000356899.2	Q16832
DDR2	ENST00000446985.6 linkuse as main transcript	c.699C>T	p.Thr233Thr	synonymous_variant	8/18	3		ENSP00000400309.2	Q16832
DDR2	ENST00000672207.1 linkuse as main transcript	n.1085C>T		non_coding_transcript_exon_variant	8/13

Frequencies

GnomAD3 genomes

AF:

0.00925

AC:

1407

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00644

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00934

AC:

2345

AN:

250958

Hom.:

AF XY:

0.00957

AC XY:

1297

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00940

Gnomad ASJ exome

AF:

0.00517

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00614

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.00997

GnomAD4 exome

AF:

0.0130

AC:

18977

AN:

1461820

Hom.:

165

Cov.:

AF XY:

0.0127

AC XY:

9262

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00230

Gnomad4 AMR exome

AF:

0.00995

Gnomad4 ASJ exome

AF:

0.00486

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00634

Gnomad4 FIN exome

AF:

0.00402

Gnomad4 NFE exome

AF:

0.0151

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.00924

AC:

1407

AN:

152216

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

671

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00231

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00645

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.0139

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.00989

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0157

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DDR2: BP4, BP7, BS1, BS2 -

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.9

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over