About DDR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DDR2 c.1723G>C, p.(Gly575Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
NM_006182.3:c.1723G>C is absent from population databases at appreciable frequency. In gnomAD v2.1 the global allele frequency is 1.42e-5 (0.00142%, 4/282,340 alleles) and in gnomAD v4.1 it is 5.58e-6 (0.00056%, 9/1,614,004 alleles). The highest subpopulation frequency is 5.65e-5 (0.00565%) in Admixed American (gnomAD v2.1). All frequencies are well below the 0.1% threshold, and no homozygotes have been observed.
PP3Supporting
PP3 · supporting
Multiple in silico tools support a deleterious effect. REVEL predicts a damaging score of 0.972 (well above the 0.75 threshold). BayesDel score of 0.558 is borderline but consistent with a deleterious prediction. SpliceAI predicts no splicing impact (max delta = 0.00), which does not contradict the missense deleterious prediction.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
9 / 1,614,004 alleles
gnomAD v4.1: 9 / 1,614,004 alleles. Recorded AF 5.57619e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41673e-05; MAF= 0.00142%, 4/282340 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.65195e-05; MAF= 0.00565%, 2/35386 alleles, homozygotes = 0); grpmax FAF= 9.59e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DDR2, a receptor tyrosine kinase, is mutated at low frequencies in various cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 4 not met · 17 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006182.3:c.1723G>C (p.Gly575Arg) is a missense variant in exon 13 of DDR2. It is extremely rare in population databases, with a global allele frequency of 1.42e-05 in gnomAD v2.1 (4/282,340 alleles) and 5.58e-06 in gnomAD v4.1 (9/1,614,004 alleles), meeting PM2 at supporting strength.
REVEL predicts a deleterious score of 0.972, meeting PP3 at supporting strength. BayesDel (0.558) is consistent with this prediction. SpliceAI predicts no splicing impact (max delta = 0.00).
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics, variation ID 4701000). No functional studies, segregation data, de novo observations, or case-control data are available for this variant.
PVS1 is not applicable as this is a missense variant; PM5 is not applicable as no pathogenic missense variant at the same residue has been identified; BP7 is not applicable as this is not a synonymous variant.
No criteria match.
Met · 2
PM2 SupportingNM_006182.3:c.1723G>C is absent from population databases at appreciable frequency. In gnomAD v2.1 the global allele frequency is 1.42e-5 (0.00142%, 4/282,340 alleles) and in gnomAD v4.1 it is 5.58e-6 (0.00056%, 9/1,614,004 alleles). The highest subpopulation frequency is 5.65e-5 (0.00565%) in Admixed American (gnomAD v2.1). All frequencies are well below the 0.1% threshold, and no homozygotes have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=1.42e-5 (4/282
- 340)
- homozygotes=0
- grpmax FAF=9.59e-6.
- gnomAD v4.1: AF=5.58e-6 (9/1
- 614
- 004)
- grpmax FAF=1.33e-5.
- Highest subpopulation: Admixed American
- AF=5.65e-5 (0.00565%)
- well below 0.1% threshold.
Sources
PP3 SupportingMultiple in silico tools support a deleterious effect. REVEL predicts a damaging score of 0.972 (well above the 0.75 threshold). BayesDel score of 0.558 is borderline but consistent with a deleterious prediction. SpliceAI predicts no splicing impact (max delta = 0.00), which does not contradict the missense deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.972 (strongly pathogenic prediction).
- BayesDel: 0.558 (borderline pathogenic prediction).
- SpliceAI: max delta = 0.00 (no predicted splicing impact).
Sources
Not met · 4 · evaluated, threshold not reached
BA1 The highest observed population allele frequency is 5.65e-5 (0.00565%) in the Admixed American subpopulation (gnomAD v2.1), which is far below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF: 5.65e-5 (0.00565%).
- gnomAD v4.1 max subpop AF: 5.00e-5 (0.00500%).
- Both far below 1% BA1 threshold.
Sources
BS1 The highest observed population allele frequency is 5.65e-5 (0.00565%) in the Admixed American subpopulation (gnomAD v2.1), which is far below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF: 5.65e-5 (0.00565%).
- gnomAD v4.1 max subpop AF: 5.00e-5 (0.00500%).
- Both far below 0.3% BS1 threshold.
Sources
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. DDR2-related spondylo-meta-epiphyseal dysplasia (SMED-SL) is caused by both missense and splice site mutations; missense variants are a recognized disease mechanism. Therefore BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- Literature confirms missense variants in DDR2 cause SMED-SL.
- Gene is not one where primarily truncating variants cause disease.
BP4 Multiple in silico tools predict a deleterious effect. REVEL score of 0.972 strongly supports pathogenicity and contradicts a benign interpretation. BP4 cannot be applied when computational evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.972 (strongly pathogenic prediction
- contrary to BP4).
- BayesDel: 0.558 (borderline pathogenic).
Sources
revelbayesdel
Not assessed · 17 · no assessment recorded
PS1 No established pathogenic variant causing the same amino acid change (p.Gly575Arg) at this position has been identified in ClinVar or the literature. PS1 cannot be assessed without such evidence. Details ▾Hide ▴
Evidence considered
- ClinVar does not list any pathogenic or likely pathogenic variant at DDR2 residue 575.
- PM5 candidate search found zero same-residue comparator variants.
Still missing
- No known pathogenic variant with the same amino acid change has been reported.
PS2 No de novo data are available for NM_006182.3:c.1723G>C. The variant has not been reported in any trio or parentage-confirmed study. Details ▾Hide ▴
Still missing
- No de novo observation reported for this variant.
PS3 No variant-specific functional studies demonstrating a damaging effect have been identified. OncoKB reports 'Unknown Oncogenic Effect' with no supporting PMIDs. No literature was found that directly tests NM_006182.3:c.1723G>C in a functional assay. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence curated.
Still missing
- No functional studies (in vitro or in vivo) have been reported for this variant.
Sources
PS4 This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics). No case-control studies, cohort analyses, or enriched case observations are available to assess PS4. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submitter
- Uncertain significance
- no case-control data.
Still missing
- No case-control or cohort prevalence data available.
Sources
PM1 Position 575 is within the DDR2 protein kinase domain (residues ~563-849), but no well-established critical functional domain with absent benign variation has been defined at this specific residue. The hotspot analysis did not identify this position as a statistically significant mutational hotspot. Without domain-specific benign variation data, PM1 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue 575 is not a statistically significant hotspot.
- Residue is within the DDR2 kinase domain but no domain-specific benign variation constraints are documented.
Still missing
- No established critical functional domain with absent benign variation defined for DDR2 residue 575.
PM6 No de novo observation has been reported for NM_006182.3:c.1723G>C. PM6 requires confirmed de novo occurrence with parentage confirmation. Details ▾Hide ▴
Still missing
- No de novo report available.
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data reported.
PP2 DDR2 is associated with spondylo-meta-epiphyseal dysplasia (SMED-SL) via both missense and truncating variants. Insufficient data are available to determine whether DDR2 has a low rate of benign missense variation such that PP2 can be applied. Details ▾Hide ▴
Evidence considered
- DDR2 disease mechanism involves missense and loss-of-function variants.
- No gene-level benign missense constraint metric is available.
Still missing
- No gene-level benign missense variation rate data available to support PP2.
PP4 No specific patient phenotype information is available for the individual(s) carrying this variant. PP4 requires that the variant carrier's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype data provided.
PP5 This variant is classified as Uncertain significance by a single clinical laboratory (Labcorp Genetics) in ClinVar. No reputable source has classified it as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 1 submitter (Labcorp Genetics)
- criteria provided
- single submitter.
Sources
BS2 No homozygous observations have been reported in gnomAD. BS2 requires observation in a healthy adult homozygous state, or in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes.
- gnomAD v4.1: 0 homozygotes.
Still missing
- No homozygous or compound heterozygous observations available.
Sources
BS3 No functional studies demonstrating a benign effect have been identified for NM_006182.3:c.1723G>C. Details ▾Hide ▴
Still missing
- No functional studies (benign or pathogenic) available for this variant.
BS4 No segregation data demonstrating lack of cosegregation with disease are available. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No observation of this variant in trans with a known pathogenic DDR2 variant has been reported. Details ▾Hide ▴
Still missing
- No trans-phase observations with pathogenic DDR2 variants available.
BP5 No case has been reported in which an alternative molecular basis for disease was identified in an individual carrying this variant. Details ▾Hide ▴
Still missing
- No cases with alternative molecular basis identified.
BP6 No reputable source classifies this variant as benign or likely benign. The sole ClinVar submission (Labcorp Genetics) classifies it as Uncertain significance. Details ▾Hide ▴
PS5 No alternative pathogenic variant at the same amino acid position (Gly575) has been identified. The PM5 candidate search returned zero same-residue comparator variants with pathogenic classification. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue pathogenic comparator variants found.
Still missing
- No pathogenic variant at the same amino acid position has been reported.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006182.3:c.1723G>C is a missense variant (p.Gly575Arg) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (c.1723G>C
- p.Gly575Arg)
- not a predicted null variant.
- pvs1_variant_assessment confirms variant bucket is 'other' and framework does not apply.
Sources
PM5 N/AUnable to confirm classic same-residue PM5 semantics; no pathogenic missense variant at the same amino acid position (Gly575) was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparator variants with pathogenic classification.
BP7 N/ABP7 applies to synonymous (silent) variants. NM_006182.3:c.1723G>C is a missense variant (p.Gly575Arg); BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Identifiers
- Gene
- DDR2
- Transcript
- NM_006182.3
- Coding (HGVS c.)
- NM_006182.3:c.1723G>C
- Protein (HGVS p.)
- NP_006173.2:p.(Gly575Arg)
- GRCh38
- chr1:162772242 G>C
- GRCh37
- chr1:162742032 G>C
- ClinVar
- 4701000
Gene diagram
Every interpreted variant in DDR2, mapped onto the exon structure of NM_006182.3. Select a row to find it on the plot.
DDR2NM_006182.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in DDR2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
9 / 1,614,004 alleles
AF 5.58e-06 · 0 homozygotes · FAF 1.33e-05
gnomAD v2.1
4 / 282,340 alleles
AF 1.42e-05 · 0 homozygotes · FAF 9.59e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.6e-06 · 9 / 1,614,004 alleles · 0 hom · FAF 1.3e-05
| Admixed American3 / 59,994 | 5e-05 |
| Remaining individuals1 / 62,484 | 1.6e-05 |
| European (non-Finnish)5 / 1,180,018 | 4.2e-06 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.4e-05 · 4 / 282,340 alleles · 0 hom · FAF 9.6e-06
| Admixed American2 / 35,386 | 5.7e-05 |
| European (non-Finnish)2 / 128,832 | 1.6e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57619e-06; MAF= 0.00056%, 9/1614004 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.0005e-05; MAF= 0.00500%, 3/59994 alleles, homozygotes = 0); grpmax FAF= 1.327e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41673e-05; MAF= 0.00142%, 4/282340 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.65195e-05; MAF= 0.00565%, 2/35386 alleles, homozygotes = 0); grpmax FAF= 9.59e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.972
- BayesDel
- 0.558
How the predictions were used
PP3 SupportingMultiple in silico tools support a deleterious effect. REVEL predicts a damaging score of 0.972 (well above the 0.75 threshold). BayesDel score of 0.558 is borderline but consistent with a deleterious prediction. SpliceAI predicts no splicing impact (max delta = 0.00), which does not contradict the missense deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.972 (strongly pathogenic prediction).
- BayesDel: 0.558 (borderline pathogenic prediction).
- SpliceAI: max delta = 0.00 (no predicted splicing impact).
Sources
BP4 Multiple in silico tools predict a deleterious effect. REVEL score of 0.972 strongly supports pathogenicity and contradicts a benign interpretation. BP4 cannot be applied when computational evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.972 (strongly pathogenic prediction
- contrary to BP4).
- BayesDel: 0.558 (borderline pathogenic).
Sources
revelbayesdel
BP7 N/ABP7 applies to synonymous (silent) variants. NM_006182.3:c.1723G>C is a missense variant (p.Gly575Arg); BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.972. BayesDel score = 0.558463.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
9 / 1,614,004 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/4701000/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-162742032-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-162772242-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-162772242-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006182.3%3Ac.1723…
- OncoKB ↗www.oncokb.org/gene/DDR2/G575R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=DDR2+c.1723G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57619e-06; MAF= 0.00056%, 9/1614004 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.0005e-05; MAF= 0.00500%, 3/59994 alleles, homozygotes = 0); grpmax FAF= 1.327e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41673e-05; MAF= 0.00142%, 4/282340 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.65195e-05; MAF= 0.00565%, 2/35386 alleles, homozygotes = 0); grpmax FAF= 9.59e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4701000)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.972. BayesDel score = 0.558463.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DDR2, a receptor tyrosine kinase, is mutated at low frequencies in various cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.