1-162759823-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
warburg-cinotti syndrome
Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Illumina, Ambry Genetics

DDR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 259935.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDR2	NM_006182.4 link	c.699C>T	p.Thr233Thr	synonymous_variant	Exon 8 of 18	ENST00000367921.8	NP_006173.2	Q16832A0A024R906

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DDR2	ENST00000367921.8 link	c.699C>T	p.Thr233Thr	synonymous_variant	Exon 8 of 18	1	NM_006182.4	ENSP00000356898.3	Q16832
DDR2	ENST00000367922.7 link	c.699C>T	p.Thr233Thr	synonymous_variant	Exon 9 of 19	1		ENSP00000356899.2	Q16832
DDR2	ENST00000446985.6 link	c.699C>T	p.Thr233Thr	synonymous_variant	Exon 8 of 18	3		ENSP00000400309.2	Q16832
DDR2	ENST00000672207.1 link	n.1085C>T		non_coding_transcript_exon_variant	Exon 8 of 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

GnomAD2 exomes

AF:

0.00934

AC:

2345

AN:

250958

AF XY:

0.00957

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 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

African (AFR)

AF:

0.00230

AC:

AN:

33478

American (AMR)

AF:

0.00995

AC:

445

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00486

AC:

127

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.00634

AC:

547

AN:

86258

European-Finnish (FIN)

AF:

0.00402

AC:

215

AN:

53418

Middle Eastern (MID)

AF:

0.00993

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0151

AC:

16839

AN:

1111978

Other (OTH)

AF:

0.0110

AC:

666

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1078

2156

3233

4311

5389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

646

1292

1938

2584

3230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00924

AC:

1407

AN:

152216

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

671

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

41522

American (AMR)

AF:

0.0145

AC:

221

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00645

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00415

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

946

AN:

68028

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DDR2: BP4, BP7, BS1, BS2 -

Jul 30, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Nov 19, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.9

(source)

DANN

Benign

0.62

PhyloP100

-1.6

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over