1-162776341-C-T

Variant names:

• chr1-162776341-C-T
• rs121964863
• NM_006182.4:c.2254C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PM1 PP2 PP3_Strong PP5 BS2

The NM_006182.4(DDR2):​c.2254C>T​(p.Arg752Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R752H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DDR2 NM_006182.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.78

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 4 ACMG points.

• PM1: In a domain Protein kinase (size 286) in uniprot entity DDR2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_006182.4
• 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, 0.982
• PP5: Variant 1-162776341-C-T is Pathogenic according to our data. Variant chr1-162776341-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12313.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDR2	NM_006182.4	c.2254C>T	p.Arg752Cys	missense_variant	Exon 16 of 18	ENST00000367921.8	NP_006173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDR2	ENST00000367921.8	c.2254C>T	p.Arg752Cys	missense_variant	Exon 16 of 18	1	NM_006182.4	ENSP00000356898.3
DDR2	ENST00000367922.7	c.2254C>T	p.Arg752Cys	missense_variant	Exon 17 of 19	1		ENSP00000356899.2
DDR2	ENST00000446985.6	c.2254C>T	p.Arg752Cys	missense_variant	Exon 16 of 18	3		ENSP00000400309.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727190

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome Pathogenic:1

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.6	.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.91		Gain of catalytic residue at W753 (P = 0.0037);Gain of catalytic residue at W753 (P = 0.0037);Gain of catalytic residue at W753 (P = 0.0037);
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.89

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: rs121964863; hg19: chr1-162746131; COSMIC: COSV63370248; COSMIC: COSV63370248;