rs115169993

chr1-162772032-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006182.4(DDR2):c.1513G>A(p.Gly505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 1,607,024 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: DDR2 NM_006182.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3 O:1
• Conservation: PhyloP100: 0.870

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DDR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.003576517).
• BP6: Variant 1-162772032-G-A is Benign according to our data. Variant chr1-162772032-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00265 (403/152274) while in subpopulation AFR AF= 0.0091 (378/41546). AF 95% confidence interval is 0.00834. There are 2 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDR2	NM_006182.4	c.1513G>A	p.Gly505Ser	missense_variant	13/18	ENST00000367921.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDR2	ENST00000367921.8	c.1513G>A	p.Gly505Ser	missense_variant	13/18	1	NM_006182.4	P1
DDR2	ENST00000367922.7	c.1513G>A	p.Gly505Ser	missense_variant	14/19	1		P1
DDR2	ENST00000446985.6	c.1513G>A	p.Gly505Ser	missense_variant	13/18	3		P1
DDR2	ENST00000433757.1	n.290G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152156 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000777 AC: 186 AN: 239252 Hom.: 1 AF XY: 0.000465 AC XY: 60 AN XY: 129070

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000508

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000571

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000746

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000252 AC: 367 AN: 1454750 Hom.: 1 Cov.: 31 AF XY: 0.000234 AC XY: 169 AN XY: 722994

Gnomad4 AFR exome AF: 0.00909

Gnomad4 AMR exome AF: 0.000410

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152274 Hom.: 2 Cov.: 33 AF XY: 0.00282 AC XY: 210 AN XY: 74454

Gnomad4 AFR AF: 0.00910

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000728 Hom.: 0

Bravo AF: 0.00299

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000824 AC: 100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 15, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

DDR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Non-small cell lung carcinoma Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.29	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.68	D
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.42	T
Polyphen		0.14	B;B;B
Vest4		0.094, 0.092
MVP		0.86
MPC		0.45
ClinPred		0.0024	T
GERP RS		2.0
Varity_R		0.032
gMVP		0.22

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: rs115169993; hg19: chr1-162741822; COSMIC: COSV63369379; COSMIC: COSV63369379;