rs35077871

Variant names:

• chr1-162780159-G-T
• rs35077871
• NM_006182.4:c.2481G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-162780159-G-T
• chr1-162780159-G-A

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.2481G>T​(p.Leu827Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,902 control chromosomes in the GnomAD database, including 27 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 0.0066 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (13 hom.)
• Consequence: DDR2 NM_006182.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.25
• Publications: 3 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=-0.48).
• BP6: Variant 1-162780159-G-T is Benign according to our data. Variant chr1-162780159-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259933.
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00658 (1001/152124) while in subpopulation AFR AF = 0.0224 (928/41518). AF 95% confidence interval is 0.0212. There are 14 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.2481G>T	p.Leu827Leu	synonymous	Exon 18 of 18	NP_006173.2	Q16832
	DDR2	NM_001014796.3		c.2481G>T	p.Leu827Leu	synonymous	Exon 19 of 19	NP_001014796.1	Q16832
	DDR2	NM_001354982.2		c.2481G>T	p.Leu827Leu	synonymous	Exon 18 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.2481G>T	p.Leu827Leu	synonymous	Exon 18 of 18	ENSP00000356898.3	Q16832
	DDR2	ENST00000367922.7	TSL:1	c.2481G>T	p.Leu827Leu	synonymous	Exon 19 of 19	ENSP00000356899.2	Q16832
	DDR2	ENST00000877159.1		c.2535G>T	p.Leu845Leu	synonymous	Exon 18 of 18	ENSP00000547218.1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1002 AN: 152006 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00163 AC: 409 AN: 251276 AF XY: 0.00113

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000653 AC: 954 AN: 1461778 Hom.: 13 Cov.: 34 AF XY: 0.000529 AC XY: 385 AN XY: 727198

African (AFR) AF: 0.0244 AC: 816 AN: 33466

American (AMR) AF: 0.000648 AC: 29 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111926

Other (OTH) AF: 0.00113 AC: 68 AN: 60390

GnomAD4 genome AF: 0.00658 AC: 1001 AN: 152124 Hom.: 14 Cov.: 31 AF XY: 0.00596 AC XY: 443 AN XY: 74362

African (AFR) AF: 0.0224 AC: 928 AN: 41518

American (AMR) AF: 0.00328 AC: 50 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67986

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00344 Hom.: 2

Bravo AF: 0.00748

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.48
CADD	Benign	7.9
DANN	Benign	0.77
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35077871; hg19: chr1-162749949;