NM_006182.4:c.187C>A

Variant names:

• chr1-162754625-C-A
• rs144594252
• NM_006182.4:c.187C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 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
• Publications: 0 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• warburg-cinotti syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DDR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.2869 (below the threshold of 3.09). Trascript score misZ: 3.8204 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
DDR2	NM_006182.4	c.187C>A	p.Leu63Met	missense_variant, splice_region_variant	Exon 5 of 18	ENST00000367921.8	NP_006173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDR2	ENST00000367921.8	c.187C>A	p.Leu63Met	missense_variant, splice_region_variant	Exon 5 of 18	1	NM_006182.4	ENSP00000356898.3

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
PhyloP100		1.8
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
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs144594252; hg19: chr1-162724415;