1-162778600-T-A

Position:

• chr1-162778600-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_006182.4(DDR2):​c.2304T>A​(p.Ser768Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDR2 NM_006182.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.291

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Protein kinase (size 286) in uniprot entity DDR2_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_006182.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DDR2. . Gene score misZ 2.2869 (greater than the threshold 3.09). Trascript score misZ 3.8204 (greater than threshold 3.09). GenCC has associacion of gene with warburg-cinotti syndrome, spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-162778600-T-A is Pathogenic according to our data. Variant chr1-162778600-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 375878.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDR2	NM_006182.4	c.2304T>A	p.Ser768Arg	missense_variant	17/18	ENST00000367921.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDR2	ENST00000367921.8	c.2304T>A	p.Ser768Arg	missense_variant	17/18	1	NM_006182.4	P1
DDR2	ENST00000367922.7	c.2304T>A	p.Ser768Arg	missense_variant	18/19	1		P1
DDR2	ENST00000446985.6	c.2304T>A	p.Ser768Arg	missense_variant	17/18	3		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Squamous cell carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Non-small cell lung carcinoma Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.5	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	.;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	.;D;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.99, 0.99
MutPred		0.90		Loss of ubiquitination at K763 (P = 0.055);Loss of ubiquitination at K763 (P = 0.055);Loss of ubiquitination at K763 (P = 0.055);
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs267598140; hg19: chr1-162748390; COSMIC: COSV63371628; COSMIC: COSV63371628;