Variant chr1-162776225-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The ENST00000367921.8(DDR2):c.2138C>A(p.Thr713Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. T713I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DDR2
ENST00000367921.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.79

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

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 ENST00000367921.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-162776225-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12315.Status of the report is no_assertion_criteria_provided, 0 stars.

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, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDR2	NM_006182.4 linkuse as main transcript	c.2138C>A	p.Thr713Lys	missense_variant	16/18	ENST00000367921.8	NP_006173.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DDR2	ENST00000367921.8 linkuse as main transcript	c.2138C>A	p.Thr713Lys	missense_variant	16/18	1	NM_006182.4	ENSP00000356898	P1
DDR2	ENST00000367922.7 linkuse as main transcript	c.2138C>A	p.Thr713Lys	missense_variant	17/19	1		ENSP00000356899	P1
DDR2	ENST00000446985.6 linkuse as main transcript	c.2138C>A	p.Thr713Lys	missense_variant	16/18	3		ENSP00000400309	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251372

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

2.9

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.9

.;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

1.0

D;D;D

Vest4

0.92, 0.92

MutPred

0.89

Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);

MVP

0.99

MPC

1.4

ClinPred

0.99

GERP RS

5.2

Varity_R

0.99

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over