About DDR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DDR2 c.298G>A, p.(Val100Met)
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
PM2Moderate
PM2 · moderate
This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (total AF=1.24e−06; 2/1,614,106 alleles; 0 homozygotes; grpmax FAF=2.8e−07), well below the 0.1% threshold for PM2 application. The highest subpopulation frequency is in European (non-Finnish) at 1.69e−06 (2/1,179,998 alleles).
PP3Supporting
PP3 · supporting
Multiple in silico prediction tools support a deleterious effect. REVEL score is 0.883 (strongly pathogenic; well above the 0.75 threshold). BayesDel score is 0.566 (intermediate, leaning deleterious). SpliceAI predicts no splicing impact (max delta=0.01), consistent with a missense-only effect. The high REVEL score provides supporting evidence for pathogenicity.
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 moderate, PP3 supporting; combination = 1 moderate + 1 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
2 / 1,614,106 alleles
gnomAD v4.1: 2 / 1,614,106 alleles. Recorded AF 1.23908e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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
Not recorded
A ClinVar laboratory submission summary was not recorded.
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 · 9 not met · 9 not assessed · 9 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.298G>A (p.Val100Met) is a missense variant in DDR2, a receptor tyrosine kinase gene in which missense variants cause spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL).
This variant is extremely rare in population databases: absent from gnomAD v2.1 and present at 2/1,614,106 alleles (AF=1.24e−06) in gnomAD v4.1, with a grpmax filtering allele frequency of 2.8e−07, meeting PM2 at moderate strength.
In silico prediction tools support a deleterious effect: REVEL score 0.883 (strongly pathogenic), meeting PP3 at supporting strength.
The variant is absent from ClinVar with no classifications from any submitter. No variant-specific functional data, de novo observations, or segregation information were available for assessment.
Available evidence includes one moderate pathogenic criterion (PM2) and one supporting pathogenic criterion (PP3). No benign criteria are met. This evidence is insufficient to classify the variant as pathogenic or likely pathogenic under the ACMG/AMP 2015 framework. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateThis variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (total AF=1.24e−06; 2/1,614,106 alleles; 0 homozygotes; grpmax FAF=2.8e−07), well below the 0.1% threshold for PM2 application. The highest subpopulation frequency is in European (non-Finnish) at 1.69e−06 (2/1,179,998 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: 2/1
- 614
- 106 alleles (AF=1.24e−06
- grpmax FAF=2.8e−07). Far below 0.1% non-VCEP PM2 threshold.
Sources
PP3 SupportingMultiple in silico prediction tools support a deleterious effect. REVEL score is 0.883 (strongly pathogenic; well above the 0.75 threshold). BayesDel score is 0.566 (intermediate, leaning deleterious). SpliceAI predicts no splicing impact (max delta=0.01), consistent with a missense-only effect. The high REVEL score provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.883 (strongly pathogenic
- >0.75). BayesDel: 0.566 (intermediate). SpliceAI: max delta=0.01 (no splice impact).
Still missing
- HCI prior not available for DDR2 to supplement in silico consensus.
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No pathogenic variant with the same amino acid change (p.Val100Met) arising from a different nucleotide substitution has been identified in ClinVar or the literature. This variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no same amino acid change reference variant available for PS1 comparison.
Still missing
- No ClinVar entries exist for DDR2 p.Val100Met from any nucleotide change.
Sources
PS3 No variant-specific functional studies or systematic range characterization that includes codon 100 were identified in the literature. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. COSMIC reports no entries for this variant in somatic cancers. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence. COSMIC: no entries. Literature pass: zero PMIDs with variant-specific data.
Still missing
- No experimental functional data for p.Val100Met or systematically characterized range including codon 100 in DDR2.
Sources
PM1 The variant p.Val100Met lies within the discoidin domain of DDR2, but it does not fall within a statistically significant mutational hotspot (cancerhotspots.org). No evidence was identified that codon 100 resides within a well-characterized functional domain lacking benign variation, which would be required to satisfy PM1 absent a hotspot designation. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant. Hotspot screen: not in a statistically significant hotspot. No domain-level benign variation constraint data available for the DDR2 discoidin domain.
Still missing
- No mutational hotspot at codon 100. No domain-level benign missense constraint data for the discoidin domain.
PP5 This variant is absent from ClinVar. No reputable source (3-star expert panel or equivalent) has classified this variant as pathogenic or likely pathogenic. There is no ClinVar submission to evaluate. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- zero submitters
- no classification
- no expert panel review.
Still missing
- No ClinVar entry exists for this variant.
Sources
BA1 The variant frequency in gnomAD v4.1 (AF=1.24e−06, 0.00012%) is orders of magnitude below the BA1 threshold of 1% (>0.01). This variant is extremely rare in the general population. Details ▾Hide ▴
BS1 The variant frequency in gnomAD v4.1 (AF=1.24e−06, 0.00012%) is well below the BS1 threshold of >0.3%. It is too rare to support a benign interpretation based on population frequency. Details ▾Hide ▴
BS3 No well-established functional studies demonstrating a neutral or benign effect for this variant were identified. OncoKB reports no reviewed functional evidence, and the literature pass returned zero PMIDs with variant-specific functional data. Details ▾Hide ▴
Evidence considered
- No functional studies showing normal protein function for p.Val100Met.
Still missing
- No benign functional data available.
Sources
BP4 Multiple in silico predictors support a deleterious rather than benign effect. REVEL score is 0.883 (strongly pathogenic). BayesDel is 0.566 (intermediate, not clearly benign). SpliceAI delta is 0.01 (no splice impact, but this does not indicate a benign effect). The computational evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.883 (damaging). BayesDel: 0.566 (not clearly benign). SpliceAI: max delta=0.01 (no splice effect
- not a benign signal).
Sources
BP6 This variant is absent from ClinVar. No reputable source has classified it as benign or likely benign. There are no expert panel benign classifications to reference. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no benign classification from any submitter.
Still missing
- No ClinVar entry exists for this variant.
Sources
Not assessed · 9 · no assessment recorded
PS2 No proband phenotype, family history, or parental genotype data were provided. De novo status cannot be evaluated without trio sequencing or confirmed parental relationships. Details ▾Hide ▴
Still missing
- No trio/parental genotype data available. Proband phenotype not provided.
PS4 No case/control data or affected-vs-unaffected prevalence statistics were provided. The variant is absent from ClinVar, precluding any submitter-based case counting. Details ▾Hide ▴
Still missing
- No proband phenotype
- no case/control cohort data
- no affected-unaffected prevalence comparison.
PM6 No de novo data or parental genotype information was available. PM6 requires confirmation that the variant arose de novo in a proband, which cannot be assessed without trio sequencing data. Details ▾Hide ▴
Still missing
- No proband phenotype
- no parental genotypes
- no de novo confirmation testing.
PP1 No family segregation data, pedigree, or co-segregation analysis was provided. PP1 cannot be evaluated without information on variant transmission in affected relatives. Details ▾Hide ▴
Still missing
- No pedigree or family segregation data available.
PP2 DDR2 missense variants are an established disease mechanism for SMED-SL (per PMID:24725993), but PP2 additionally requires evidence of a low rate of benign missense variation in the gene (high missense constraint). The HCI prior is not available for DDR2, and gnomAD missense constraint metrics (Z-score) were not provided in the evidence brief. Details ▾Hide ▴
Evidence considered
- DDR2 missense mechanism for SMED-SL confirmed (PMID:24725993). HCI prior: gene not supported. No missense constraint Z-score available in evidence brief.
Still missing
- Missing gnomAD missense constraint metric (Z-score
- o/e) to determine low rate of benign missense variation.
Sources
pvs1_gene_context
PP4 No proband phenotype or clinical information was provided. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene (SMED-SL for DDR2), which cannot be evaluated without clinical data. Details ▾Hide ▴
Still missing
- Proband phenotype and clinical history not provided.
BS2 No information was provided about whether this variant has been observed in healthy adults at an age when full penetrance of DDR2-related disease (SMED-SL) would be expected. Without clinical phenotype data for the 2 gnomAD carriers, BS2 cannot be applied. Details ▾Hide ▴
Still missing
- No phenotype data for gnomAD carriers
- cannot confirm observation in healthy adults with full penetrance expected.
BS4 No family segregation data were provided. BS4 requires non-segregation of the variant with disease in affected family members, which cannot be evaluated without pedigree information. Details ▾Hide ▴
Still missing
- No pedigree or family segregation data available.
BP2 No phase data or co-occurrence information with a known pathogenic variant in DDR2 was available. BP2 cannot be evaluated without trans-phase confirmation. Details ▾Hide ▴
Still missing
- No variant phasing data or co-occurrence with known pathogenic DDR2 variant.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006182.3:c.298G>A (p.Val100Met) is a missense variant and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant p.Val100Met
- variant does not meet PVS1 null-variant criteria per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. No evidence of biallelic DDR2 variants or trans-phase data was available. Details ▾Hide ▴
Evidence considered
- No trans-phase data
- single heterozygous variant context.
PM4 N/APM4 applies to protein-length changing variants (in-frame deletions/insertions, stop-loss). NM_006182.3:c.298G>A is a missense substitution and does not alter protein length. Details ▾Hide ▴
Evidence considered
- Missense substitution
- PM4 restricted to protein-length altering variants.
PM5 N/ANo same-residue comparator variants (different missense change at codon 100) classified as pathogenic or likely pathogenic were identified in ClinVar. The automated PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting: zero same-residue comparators at DDR2 residue 100 in ClinVar.
Still missing
- No pathogenic/likely pathogenic missense variants at codon 100 with a different amino acid change.
Sources
pm5_candidatesclinvar ↗
BP1 N/ABP1 applies to missense variants in genes where only truncating variants are a known disease mechanism. DDR2 missense variants are an established cause of SMED-SL (PMID:24725993: 'SMED-SL is reported to be caused by missense or splice site mutations in DDR2'), so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- PMID:24725993 confirms DDR2 missense variants cause SMED-SL
- missense is a known disease mechanism.
Sources
pvs1_gene_context
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. NM_006182.3:c.298G>A is a substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 restricted to in-frame indels in repeat regions.
BP5 N/ABP5 applies when a variant is found in a case with an alternate molecular basis for disease. No alternate molecular diagnosis was identified or provided for this case. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis identified.
BP7 N/ANM_006182.3:c.298G>A is a missense variant (p.Val100Met), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. SpliceAI delta of 0.01 confirms no cryptic splice effect, but the criterion is categorically inapplicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous variants. SpliceAI max delta=0.01 confirms no splice alteration.
Sources
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. The established criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5, BA1, BS1-BS4, and BP1-BP7. No CSPEC/VCEP framework applies a PS5 criterion for DDR2. Details ▾Hide ▴
Evidence considered
- PS5 is absent from the ACMG/AMP 2015 classification framework (PMID:25741868).
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- DDR2
- Transcript
- NM_006182.3
- Coding (HGVS c.)
- NM_006182.3:c.298G>A
- Protein (HGVS p.)
- NP_006173.2:p.(Val100Met)
- GRCh38
- chr1:162754736 G>A
- GRCh37
- chr1:162724526 G>A
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
2 / 1,614,106 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,106 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,179,998 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23908e-06; MAF= 0.00012%, 2/1614106 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69492e-06; MAF= 0.00017%, 2/1179998 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.883
- BayesDel
- 0.566
How the predictions were used
PP3 SupportingMultiple in silico prediction tools support a deleterious effect. REVEL score is 0.883 (strongly pathogenic; well above the 0.75 threshold). BayesDel score is 0.566 (intermediate, leaning deleterious). SpliceAI predicts no splicing impact (max delta=0.01), consistent with a missense-only effect. The high REVEL score provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.883 (strongly pathogenic
- >0.75). BayesDel: 0.566 (intermediate). SpliceAI: max delta=0.01 (no splice impact).
Still missing
- HCI prior not available for DDR2 to supplement in silico consensus.
Sources
BP4 Multiple in silico predictors support a deleterious rather than benign effect. REVEL score is 0.883 (strongly pathogenic). BayesDel is 0.566 (intermediate, not clearly benign). SpliceAI delta is 0.01 (no splice impact, but this does not indicate a benign effect). The computational evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.883 (damaging). BayesDel: 0.566 (not clearly benign). SpliceAI: max delta=0.01 (no splice effect
- not a benign signal).
Sources
BP7 N/ANM_006182.3:c.298G>A is a missense variant (p.Val100Met), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. SpliceAI delta of 0.01 confirms no cryptic splice effect, but the criterion is categorically inapplicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous variants. SpliceAI max delta=0.01 confirms no splice alteration.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.883. BayesDel score = 0.566277.
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
2 / 1,614,106 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
Captured ClinVar source record
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/?term=NM_006182.3%3Ac.298G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-162724526-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-162754736-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-162754736-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006182.3%3Ac.298G…
- OncoKB ↗www.oncokb.org/gene/DDR2/V100M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=DDR2+c.298G%3EA
- 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= 1.23908e-06; MAF= 0.00012%, 2/1614106 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69492e-06; MAF= 0.00017%, 2/1179998 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.883. BayesDel score = 0.566277.
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.