Genetic Variant DDR2:c.83-4C>T (chr1-162753091-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006182.4(DDR2):c.83-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,612,678 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 18 hom. )

Consequence

DDR2
NM_006182.4 splice_region, intron

Scores

Splicing: ADA: 0.001425

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.185

Publications

2 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: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
warburg-cinotti syndrome
Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina

DDR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 1-162753091-C-T is Benign according to our data. Variant chr1-162753091-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 729660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1540/152236) while in subpopulation AFR AF = 0.0354 (1472/41544). AF 95% confidence interval is 0.0339. There are 25 homozygotes in GnomAd4. There are 703 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 Unknown,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006182.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DDR2	NM_006182.4	MANE Select	c.83-4C>T	splice_region intron	N/A	NP_006173.2	Q16832
DDR2	NM_001014796.3		c.83-4C>T	splice_region intron	N/A	NP_001014796.1	Q16832
DDR2	NM_001354982.2		c.83-4C>T	splice_region intron	N/A	NP_001341911.1	Q16832

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DDR2	ENST00000367921.8	TSL:1 MANE Select	c.83-4C>T	splice_region intron	N/A	ENSP00000356898.3	Q16832
DDR2	ENST00000367922.7	TSL:1	c.83-4C>T	splice_region intron	N/A	ENSP00000356899.2	Q16832
DDR2	ENST00000877159.1		c.83-4C>T	splice_region intron	N/A	ENSP00000547218.1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1524

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00283

AC:

710

AN:

250988

AF XY:

0.00211

show subpopulations

Gnomad AFR exome

AF:

0.0391

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00107

AC:

1557

AN:

1460442

Hom.:

Cov.:

AF XY:

0.000965

AC XY:

701

AN XY:

726606

show subpopulations

African (AFR)

AF:

0.0364

AC:

1219

AN:

33444

American (AMR)

AF:

0.00168

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39650

South Asian (SAS)

AF:

0.000151

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00369

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000621

AC:

AN:

1111056

Other (OTH)

AF:

0.00260

AC:

157

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.0101

AC:

1540

AN:

152236

Hom.:

Cov.:

AF XY:

0.00944

AC XY:

703

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0354

AC:

1472

AN:

41544

American (AMR)

AF:

0.00294

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68010

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

155

232

310

387

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:

0.00530

Hom.:

Bravo

AF:

0.0113

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Connective tissue disorder (1)

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

7.3

(source)

DANN

Benign

0.87

PhyloP100

-0.18

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.046

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over