1-162753097-A-C

Position:

• chr1-162753097-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006182.4(DDR2):​c.85A>C​(p.Ile29Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DDR2 NM_006182.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07910958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDR2	NM_006182.4	c.85A>C	p.Ile29Leu	missense_variant, splice_region_variant	4/18	ENST00000367921.8	NP_006173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDR2	ENST00000367921.8	c.85A>C	p.Ile29Leu	missense_variant, splice_region_variant	4/18	1	NM_006182.4	ENSP00000356898	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460956 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 20, 2020

The DDR2 c.85A>C; p.Ile29Leu variant, to our knowledge, is not reported in the medical literature or gene specific databases.This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The isoleucine at codon 29 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ile29Leu variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.86	.;D;.;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.079	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.2	L;.;L;L
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.080	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.25, 0.25
MutPred		0.24		Loss of catalytic residue at L34 (P = 0.1009);Loss of catalytic residue at L34 (P = 0.1009);Loss of catalytic residue at L34 (P = 0.1009);Loss of catalytic residue at L34 (P = 0.1009);
MVP		0.58
MPC		0.44
ClinPred		0.13	T
GERP RS		-5.2
Varity_R		0.11
gMVP		0.48

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: rs775988877; hg19: chr1-162722887;