Classification rationale

PVS1PM2 BP4 VUS

COL4A2 c.4183C>T nonsense · exon 44

PVS1 (Very Strong): nonsense variant truncates the protein at residue 1395 of ~1712, removing the essential triple-helix and NC1 domains, consistent with nonsense-mediated decay or severe loss of function. PM2 (Supporting): ultra-rare in populations, with a single gnomAD v4.1 allele and absence from gnomAD v2.1 and gnomAD-Canada. BP4 (Supporting): SpliceAI predicts no splice impact (max delta 0.019), well below the 0.2 high-recall cutoff. Final classification: VUS, per the generic ACMG/AMP combination rule, where conflicting evidence (PVS1 very strong vs. PM2 and BP4 supporting) does not reach any pathogenic or benign classification.

PVS1 + PM2 + BP4 → VUS

Gene diagram · NM_001846.4 · variants mapped to exon structure

COL4A2 NM_001846.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong review Pathogenic

Met: nonsense variant truncates the protein at residue 1395 of ~1712, removing the essential triple-helix and NC1 domains, consistent with loss of function.

pvs1_variant_assessment classifies the variant as consequence_class 'nonsense', variant_bucket 'nonsense', with framework_source PMC6185798 and suggested_default_strength 'PVS1'.pvs1_gene_context reports germline_disease_context_found=true, lof_mechanism_supported=true, and pvs1_gene_gate='eligible' for COL4A2, based on targeted literature review of germline disease-focused publications.PMID:41499643 (Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations) reports a compound heterozygous case where a COL4A2 frameshift variant p.(Gly1426Argfs*30), predicted to cause loss of function via truncated transcript or NMD, was classified ACMG Class-IV likely pathogenic with PVS1 applied, supporting that truncating/LoF variants in COL4A2 are an accepted pathogenic mechanism.

pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

Met at supporting: only one gnomAD v4.1 allele and absence from gnomAD v2.1 and gnomAD-Canada.

No COL4A2-specific VCEP/CSPEC population-frequency specification was retrieved, so generic ACMG/AMP assessment was used.gnomAD v4.1 reports one allele among 1,613,616 total alleles (AF 6.197261306283528e-07), no homozygotes, and a highest reported major-ancestry frequency of 8.476961314539345e-07 in non-Finnish Europeans.The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met at supporting: SpliceAI predicts no splice impact (max delta 0.019), well below the 0.2 high-recall cutoff.

evidence.json spliceai block: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).' Scores: DS_AG=0.0, DS_AL=0.013, DS_DG=0.001, DS_DL=0.019, max_delta_score=0.019.SpliceAI high-recall threshold of 0.2 for a splice-altering prediction is defined in the tool's original publication: Jaganathan K et al., 'Predicting Splicing from Primary Sequence with Deep Learning', Cell 2019, PMID 30661751. The observed max delta (0.019) is well below this threshold.This variant (p.(Gln1395Ter)) is a nonsense/stop-gain change, so the missense in-silico predictor path (REVEL/BayesDel/aGVGD) is not applicable and was not used to support BP4.

spliceai ↗

Assessed · not applied · 7 not met · 10 not assessed

Pathogenic

PS2 Not met: inheritance is reported as paternal origin, not a confirmed de novo occurrence, and parental testing documentation is absent.

PS3 Not assessed: no functional assay data for this variant (e.g., collagen IV secretion or trimer assembly studies) were available.

PS4 Not assessed: no case-control or enrichment data for this variant exist; the single ClinVar submission is not case-control evidence.

PM3 Not assessed: no affected proband observed with a pathogenic COL4A2 variant in trans; phase information is unavailable.

PM6 Not met: inheritance is reported as paternal origin, not an assumed de novo occurrence; parental genotypes are undocumented.

PP1 Not assessed: no informative relatives, pedigrees, or meioses were provided; paternal origin alone is not cosegregation evidence.

PP3 Not met: missense in-silico tools do not apply to this nonsense variant, and SpliceAI impact is low (max delta 0.019).

PP4 Not assessed: no phenotype for the tested individual was provided.

PP5 Not met: the sole ClinVar submission is Likely pathogenic from one clinical laboratory, not an expert panel.

Benign

BA1 Not met: allele frequency is far below any stand-alone benign population-frequency range.

BS1 Not met: maximum observed allele frequency (8.5e-07) is far below any benign frequency threshold.

BS2 Not assessed: population data show no homozygotes and no confirmed unaffected, age-appropriate individuals.

BS3 Not assessed: no functional studies demonstrating normal function for this variant were available.

BS4 Not assessed: paternal origin does not establish whether genotype-positive relatives are clinically unaffected.

BP2 Not assessed: no documented cis or trans co-occurrence with a pathogenic variant; paternal origin alone establishes neither.

BP5 Not assessed: no individual phenotype, molecular diagnosis, or alternative molecular cause is provided.

BP6 Not met: no expert-panel benign assertion exists; the sole ClinVar submission is Likely pathogenic from a non-expert laboratory.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19726e-07; MAF= 0.00006%, 1/1613616 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47696e-07; MAF= 0.00008%, 1/1179668 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,616
0 hom

European (non-Finnish)

1 / 1,179,668

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1713186)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.66.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR