rs56351141

Variant names:

• chr1-162759823-C-T
• rs56351141
• NM_006182.4:c.699C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.56
• Publications: 5 publications found

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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• warburg-cinotti syndrome

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Illumina

ACMG classification

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 AR,AD,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDR2	NM_006182.4	MANE Select	c.699C>T	p.Thr233Thr	synonymous	Exon 8 of 18	NP_006173.2	Q16832
	DDR2	NM_001014796.3		c.699C>T	p.Thr233Thr	synonymous	Exon 9 of 19	NP_001014796.1	Q16832
	DDR2	NM_001354982.2		c.699C>T	p.Thr233Thr	synonymous	Exon 8 of 18	NP_001341911.1	Q16832

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDR2	ENST00000367921.8	TSL:1 MANE Select	c.699C>T	p.Thr233Thr	synonymous	Exon 8 of 18	ENSP00000356898.3	Q16832
	DDR2	ENST00000367922.7	TSL:1	c.699C>T	p.Thr233Thr	synonymous	Exon 9 of 19	ENSP00000356899.2	Q16832
	DDR2	ENST00000877159.1		c.699C>T	p.Thr233Thr	synonymous	Exon 8 of 18	ENSP00000547218.1

Frequencies

GnomAD3 genomes AF: 0.00925 AC: 1407 AN: 152100 Hom.: 10 Cov.: 32

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

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.: 31 AF XY: 0.0127 AC XY: 9262 AN XY: 727216

African (AFR) AF: 0.00230 AC: 77 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: 4 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: 57 AN: 5742

European-Non Finnish (NFE) AF: 0.0151 AC: 16839 AN: 1111978

Other (OTH) AF: 0.0110 AC: 666 AN: 60394

GnomAD4 genome AF: 0.00924 AC: 1407 AN: 152216 Hom.: 10 Cov.: 32 AF XY: 0.00902 AC XY: 671 AN XY: 74418

African (AFR) AF: 0.00231 AC: 96 AN: 41522

American (AMR) AF: 0.0145 AC: 221 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00645 AC: 31 AN: 4808

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0139 AC: 946 AN: 68028

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.0112 Hom.: 8

Bravo AF: 0.00989

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0157

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Connective tissue disorder (1)
-	-	1	not specified (1)
-	1	-	Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.9
DANN	Benign	0.62
PhyloP100		-1.6
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs56351141; hg19: chr1-162729613; COSMIC: COSV63371417; COSMIC: COSV63371417;