1-162778600-T-G

Position:

• chr1-162778600-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PP2 PP3_Strong

The NM_006182.4(DDR2):​c.2304T>G​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDR2 NM_006182.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 13 ACMG points.

• PS1: Transcript NM_006182.4 (DDR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 375878
• 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

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.86	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	0.83
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)		0.12		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;