About DDR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DDR2 c.1753A>G, p.(Met585Val)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD-Canada and extremely rare in general population databases (gnomAD v2.1: 5/282,840 alleles, AF=0.00177%; gnomAD v4.1: 44/1,613,842 alleles, AF=0.00273%). Both frequencies are well below the 0.1% PM2 threshold. No homozygotes observed in any population.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple in silico predictors consistently support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative value consistent with benign), and SpliceAI max delta 0.01 (no splicing alteration predicted). All three computational tools agree on lack of damaging impact.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
44 / 1,613,842 alleles
gnomAD v4.1: 44 / 1,613,842 alleles. Recorded AF 2.72641e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.76778e-05; MAF= 0.00177%, 5/282840 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00481e-05; MAF= 0.00400%, 1/24970 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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.
29 criteria with recorded statuses: 2 met · 8 not met · 12 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is a missense substitution (c.1753A>G, p.Met585Val) in DDR2, a receptor tyrosine kinase associated with autosomal recessive spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL).
The variant is extremely rare in large population databases: present in 5 of 282,840 alleles in gnomAD v2.1 (AF=0.00177%) and 44 of 1,613,842 alleles in gnomAD v4.1 (AF=0.00273%), with no homozygotes observed. It is absent from gnomAD-Canada.
Multiple in silico predictors (REVEL 0.261, BayesDel -0.199, SpliceAI max delta 0.01) consistently suggest a benign impact on protein function and splicing.
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics). No expert panel has reviewed this variant.
No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified in the literature or databases.
All publications associated with this variant through ClinVar are general policy statements on newborn screening and carrier screening; none mention DDR2 or the specific variant NM_006182.3:c.1753A>G.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD-Canada and extremely rare in general population databases (gnomAD v2.1: 5/282,840 alleles, AF=0.00177%; gnomAD v4.1: 44/1,613,842 alleles, AF=0.00273%). Both frequencies are well below the 0.1% PM2 threshold. No homozygotes observed in any population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00177% (5/282
- 840
- 0 hom)
- gnomAD v4.1 AF=0.00273% (44/1
- 613
- 842
- gnomAD-Canada absent (0/0).
Sources
BP4 SupportingMultiple in silico predictors consistently support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative value consistent with benign), and SpliceAI max delta 0.01 (no splicing alteration predicted). All three computational tools agree on lack of damaging impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.261
- BayesDel=-0.199
- SpliceAI max delta=0.01. All predictors agree: no damaging effect.
Sources
Not met · 8 · evaluated, threshold not reached
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls. The variant is extremely rare in gnomAD but no disease-specific prevalence data exist. ClinVar contains only a single uncertain significance submission. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 5/282
- 840 alleles (AF=0.00177%)
- gnomAD v4.1: 44/1
- 613
- 842 alleles (AF=0.00273%)
- ClinVar: single VUS submission by Ambry Genetics.
Still missing
- No case-control or association data
- no phenotype-specific cohort studies.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot or a well-established critical functional domain without benign variation. Hotspot assessment confirms the residue is not in a significant hotspot. Details ▾Hide ▴
Evidence considered
- Residue 585 not in a statistically significant hotspot per hotspots assessment
- exact_variant_listed: no.
Still missing
- No domain-specific analysis with benign variation data available.
PP3 Multiple in silico predictors support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative, consistent with benign), and SpliceAI max delta 0.01 (no predicted splicing impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL=0.261 (benign range)
- BayesDel=-0.199 (benign-leaning)
- SpliceAI max delta=0.01 (no splicing impact).
Sources
PP5 This variant is reported in ClinVar as Uncertain Significance by a single clinical laboratory (Ambry Genetics). PP5 requires classification as pathogenic by a reputable source; a single VUS submission does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar: single submission
- Ambry Genetics
- VUS (SCV004855152)
- review status: criteria provided
- single submitter.
Still missing
- No multiple-submitter or expert-panel classification.
Sources
BA1 The maximum population allele frequency for this variant is 0.00400% (gnomAD v2.1 African/African American subpopulation), far below the 1% BA1 threshold for benign standing. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF=7.01e-06 (0.000701%)
- v4.1 grpmax FAF=2.585e-05 (0.00259%). All well below 1%.
Sources
BS1 The maximum population allele frequency is 0.00400% (gnomAD v2.1 African/African American subpopulation), far below the 0.3% BS1 threshold for a benign allele frequency. Details ▾Hide ▴
Evidence considered
- Max subpopulation AF=4.00e-05 (0.004%)
- well below 0.3%.
Sources
BS2 No homozygous individuals observed in gnomAD v2.1 or v4.1. No evidence of observation in healthy adults lacking the DDR2-related phenotype. BS2 requires homozygous observation or observation in unaffected adults in a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 homozygotes=0
- gnomAD v4.1 homozygotes=0.
Still missing
- No homozygous observations
- no healthy-adult screening data.
Sources
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. In DDR2, both missense and truncating variants are established causes of SMED-SL; missense variants are a known disease mechanism, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- SMED-SL is caused by both missense and splice site mutations in DDR2 (PMID:24725993)
- missense is an established disease mechanism.
Sources
pvs1_gene_context
Not assessed · 12 · no assessment recorded
PS1 No evidence of a different nucleotide change at codon 585 producing the same amino acid substitution (Met585Val) that has been characterized as pathogenic. PS1 requires a different variant at the same residue with the same amino acid change that is established pathogenic. Details ▾Hide ▴
Evidence considered
- No ClinVar entries identified with a different nucleotide change producing M585V.
Still missing
- No same-residue pathogenic comparator available.
PS2 No de novo data available for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or literature.
Still missing
- No parental or de novo data available.
PS3 No variant-specific functional studies identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and has no reviewed functional evidence. No publications reporting functional characterization of p.Met585Val were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data.
Still missing
- No functional studies (in vitro or in vivo) for this variant.
Sources
PM6 No de novo data available. PM6 requires confirmed de novo occurrence without confirmed maternity/paternity. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or literature.
Still missing
- No parental or de novo data available.
PP1 No segregation data available. PP1 requires co-segregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No segregation or family data identified.
Still missing
- No familial or segregation data available.
PP2 PP2 requires evidence that missense variants are a common mechanism of disease in DDR2 and that the gene has a low rate of benign missense variation. While DDR2 missense variants are associated with SMED-SL, gene-level missense constraint metrics (e.g., Z-score, missense pLI) are not available in this case. Details ▾Hide ▴
Evidence considered
- DDR2 missense variants reported in SMED-SL
- no gene-level missense constraint data available.
Still missing
- No missense constraint Z-score or comparable metric available.
PP4 No detailed phenotype or clinical data available for individuals carrying this variant. PP4 requires the variant to be observed in a patient with a phenotype that is highly specific for DDR2-related disease. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available.
Still missing
- No individual-level clinical information.
BS3 No functional studies demonstrating a lack of damaging effect have been identified for this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data.
Still missing
- No functional studies demonstrating neutral effect.
Sources
BS4 No segregation data available to demonstrate lack of co-segregation with disease. BS4 requires observation of non-segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No familial or segregation data available.
BP2 No data on observation in trans with a known pathogenic DDR2 variant. BP2 requires observation in trans (or in cis with or without) a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Evidence considered
- No allelic phase data available.
Still missing
- No observations in trans with a pathogenic variant.
BP5 No case identified with an alternate molecular basis for disease. BP5 requires observation in a case where an alternate cause is found. Details ▾Hide ▴
Evidence considered
- No alternate-molecular-basis data available.
Still missing
- No data on alternate causes in carriers.
BP6 No reputable source reports this variant as benign. BP6 requires a reputable source reporting the variant as benign. ClinVar classifies it as VUS, not benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance.
Still missing
- No reputable benign classification.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.1753A>G, p.Met585Val); not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework per ClinGen SVI recommendations (PMC6185798) requires a null-variant bucket for default applicability. This variant falls into the 'other' bucket and does not qualify for PVS1. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 585
- variant_bucket: other
- apply_generic_pvs1_framework: false per pvs1_variant_assessment.
Sources
PM3 N/AInsufficient data to assess recessive inheritance. PM3 requires observation in trans with a pathogenic variant. No phase data available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant type is a substitution; PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss) — not applicable to single-nucleotide missense substitutions. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variant at codon 585 of DDR2 that is pathogenic was identified in ClinVar. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidate file returned 0 same-residue candidates
- eligible_for_classic_pm5_search: false.
Sources
pm5_candidates
BP3 N/AVariant type is a substitution; BP3 applies to in-frame deletions/insertions in repetitive regions — not applicable to single-nucleotide substitutions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a missense variant (c.1753A>G, p.Met585Val), not synonymous, so BP7 is not applicable regardless of SpliceAI predictions. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Met585Val)
- not synonymous
- BP7 limited to synonymous variants.
PS5 N/APS5 requires a different nucleotide change at the same codon causing a different pathogenic missense change. No such comparator has been identified for codon 585 of DDR2. Details ▾Hide ▴
Evidence considered
- No pathogenic variant at codon 585 identified in ClinVar.
Identifiers
- Gene
- DDR2
- Transcript
- NM_006182.3
- Coding (HGVS c.)
- NM_006182.3:c.1753A>G
- Protein (HGVS p.)
- NP_006173.2:p.(Met585Val)
- GRCh38
- chr1:162773493 A>G
- GRCh37
- chr1:162743283 A>G
- ClinVar
- 3080827
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
44 / 1,613,842 alleles
AF 2.73e-05 · 0 homozygotes · FAF 2.59e-05
gnomAD v2.1
5 / 282,840 alleles
AF 1.77e-05 · 0 homozygotes · FAF 7.01e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.7e-05 · 44 / 1,613,842 alleles · 0 hom · FAF 2.6e-05
| European (non-Finnish)41 / 1,179,892 | 3.5e-05 |
| Remaining individuals2 / 62,456 | 3.2e-05 |
| African/African American1 / 74,918 | 1.3e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 1.8e-05 · 5 / 282,840 alleles · 0 hom · FAF 7e-06
| African/African American1 / 24,970 | 4e-05 |
| European (non-Finnish)4 / 129,156 | 3.1e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.72641e-05; MAF= 0.00273%, 44/1613842 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.47489e-05; MAF= 0.00347%, 41/1179892 alleles, homozygotes = 0); grpmax FAF= 2.585e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.76778e-05; MAF= 0.00177%, 5/282840 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00481e-05; MAF= 0.00400%, 1/24970 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.261
- BayesDel
- -0.200
How the predictions were used
BP4 SupportingMultiple in silico predictors consistently support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative value consistent with benign), and SpliceAI max delta 0.01 (no splicing alteration predicted). All three computational tools agree on lack of damaging impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.261
- BayesDel=-0.199
- SpliceAI max delta=0.01. All predictors agree: no damaging effect.
Sources
PP3 Multiple in silico predictors support a benign interpretation: REVEL score 0.261 (below the 0.5 pathogenic threshold), BayesDel score -0.199 (negative, consistent with benign), and SpliceAI max delta 0.01 (no predicted splicing impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL=0.261 (benign range)
- BayesDel=-0.199 (benign-leaning)
- SpliceAI max delta=0.01 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a missense variant (c.1753A>G, p.Met585Val), not synonymous, so BP7 is not applicable regardless of SpliceAI predictions. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Met585Val)
- not synonymous
- BP7 limited to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.261. BayesDel score = -0.199945.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.ACMG position statement on prenatal and preconception expanded carrier screening. Discusses general principles of carrier screening; does not mention DDR2 or any specific DDR2 variant.Does not name this variant
-
PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.Cornel MC et al. · 2014Expert opinion document on neonatal screening policies in the European Union. Discusses framework for national screening policy debate; does not mention DDR2 or any specific DDR2 variant.Does not name this variant
-
PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015Position statement on whole-genome sequencing in newborn screening. Argues for continued importance of targeted approaches; does not mention DDR2 or any specific DDR2 variant.Does not name this variant
-
PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.Langer A et al. · 2012Guidelines for assessing methodological quality of economic evaluations of newborn screening programs. Does not mention DDR2 or any specific DDR2 variant.Does not name this variant
-
PMID 31022120 ↗ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.ACOG Committee Opinion on newborn screening and the role of the obstetrician-gynecologist. Does not mention DDR2 or any specific DDR2 variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
44 / 1,613,842 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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/3080827/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-162743283-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-162773493-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-162773493-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006182.3%3Ac.1753…
- OncoKB ↗www.oncokb.org/gene/DDR2/M585V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=DDR2+c.1753A%3EG
- 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= 2.72641e-05; MAF= 0.00273%, 44/1613842 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.47489e-05; MAF= 0.00347%, 41/1179892 alleles, homozygotes = 0); grpmax FAF= 2.585e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.76778e-05; MAF= 0.00177%, 5/282840 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00481e-05; MAF= 0.00400%, 1/24970 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3080827)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.261. BayesDel score = -0.199945.
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.