1-162772004-C-G

Variant names:

• chr1-162772004-C-G
• rs3738807
• NM_006182.4:c.1505-20C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006182.4(DDR2):​c.1505-20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,428,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DDR2 NM_006182.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42
• Publications: 8 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, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• warburg-cinotti syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.1505-20C>G		intron	N/A	NP_006173.2	Q16832
	DDR2	NM_001014796.3		c.1505-20C>G		intron	N/A	NP_001014796.1	Q16832
	DDR2	NM_001354982.2		c.1505-20C>G		intron	N/A	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.1505-20C>G		intron	N/A	ENSP00000356898.3	Q16832
	DDR2	ENST00000367922.7	TSL:1	c.1505-20C>G		intron	N/A	ENSP00000356899.2	Q16832
	DDR2	ENST00000877159.1		c.1559-20C>G		intron	N/A	ENSP00000547218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1428326 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707748

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32720

American (AMR) AF: 0.00 AC: 0 AN: 39510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37804

South Asian (SAS) AF: 0.00 AC: 0 AN: 82138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4518

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095378

Other (OTH) AF: 0.00 AC: 0 AN: 59116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.014
DANN	Benign	0.27
PhyloP100		-2.4

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3738807;

hg19: chr1-162741794;