chr1-162719091-G-A

Variant names:

• chr1-162719091-G-A
• rs775402435
• NM_006182.4:c.28G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006182.4(DDR2):​c.28G>A​(p.Val10Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DDR2 NM_006182.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0800
• Publications: 1 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: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• warburg-cinotti syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06390849).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006182.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDR2	NM_006182.4	MANE Select	c.28G>A	p.Val10Met	missense	Exon 3 of 18	NP_006173.2	Q16832
	DDR2	NM_001014796.3		c.28G>A	p.Val10Met	missense	Exon 4 of 19	NP_001014796.1	Q16832
	DDR2	NM_001354982.2		c.28G>A	p.Val10Met	missense	Exon 3 of 18	NP_001341911.1	Q16832

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDR2	ENST00000367921.8	TSL:1 MANE Select	c.28G>A	p.Val10Met	missense	Exon 3 of 18	ENSP00000356898.3	Q16832
	DDR2	ENST00000367922.7	TSL:1	c.28G>A	p.Val10Met	missense	Exon 4 of 19	ENSP00000356899.2	Q16832
	DDR2	ENST00000877159.1		c.28G>A	p.Val10Met	missense	Exon 3 of 18	ENSP00000547218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251136 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.080
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.28		Loss of catalytic residue at V10 (P = 0.1218)
MVP		0.64
MPC		0.44
ClinPred		0.039	T
GERP RS		-0.23
Varity_R		0.033
gMVP		0.15
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs775402435; hg19: chr1-162688881;