rs144594252

Positions:

• chr1-162754625-C-A
• chr1-162754625-C-G
• chr1-162754625-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_006182.4(DDR2):​c.187C>A​(p.Leu63Met) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L63V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDR2 NM_006182.4 missense, splice_region
• Scores: Splicing: ADA: 0.009830
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-162754625-C-G is described in Lovd as [Likely_pathogenic].
• 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, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDR2	NM_006182.4	c.187C>A	p.Leu63Met	missense_variant, splice_region_variant	5/18	ENST00000367921.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDR2	ENST00000367921.8	c.187C>A	p.Leu63Met	missense_variant, splice_region_variant	5/18	1	NM_006182.4	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	Benign	0.29
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.;D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.67, 0.67
MutPred		0.79		Gain of methylation at K59 (P = 0.0751);Gain of methylation at K59 (P = 0.0751);Gain of methylation at K59 (P = 0.0751);Gain of methylation at K59 (P = 0.0751);
MVP		0.92
MPC		1.3
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.91
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0098
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-162724415;