Variant classification summary

NM_001846.4: c.4183C>T

COL4A2 · NP_001837.2:p.(Gln1395Ter) · NM_001846.4

GRCh37: chr13:111156238 C>T · GRCh38: chr13:110503891 C>T

Gene: COL4A2 Transcript: NM_001846.4

Final call

VUS

PVS1 very strong PM2 supporting BP4 supporting

Variant details

Gene

COL4A2

Transcript

NM_001846.4

Protein

NP_001837.2:p.(Gln1395Ter)

gnomAD AF

6.197261306283528e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

PM2 (Supporting): ultra-rare in populations, with a single gnomAD v4.1 allele and absence from gnomAD v2.1 and gnomAD-Canada.

3

BP4 (Supporting): SpliceAI predicts no splice impact (max delta 0.019), well below the 0.2 high-recall cutoff.

4

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.

Final determination: PVS1 + 1 supporting pathogenic criterion with concurrent 1 supporting benign criterion = conflicting evidence → Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Not applicable: this nonsense variant creates no altered amino acid to compare against a previously established pathogenic missense.	generic_acmg_combination_rules
PS2	Not met	Not met: inheritance is reported as paternal origin, not a confirmed de novo occurrence, and parental testing documentation is absent.	clinvar
PS3	Not assessed	Not assessed: no functional assay data for this variant (e.g., collagen IV secretion or trimer assembly studies) were available.
PS4	Not assessed	Not assessed: no case-control or enrichment data for this variant exist; the single ClinVar submission is not case-control evidence.	clinvar
PM1	N/A	Not applicable: PM1 requires a missense change; this nonsense variant introduces no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met at supporting: only one gnomAD v4.1 allele and absence from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband observed with a pathogenic COL4A2 variant in trans; phase information is unavailable.	clinvar PMID:25741868
PM4	N/A	Not applicable: the variant does not change protein length, so the in-frame/stop-loss premise does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at residue 1395 to compare against a pathogenic missense at the same position.	generic_acmg_combination_rules
PM6	Not met	Not met: inheritance is reported as paternal origin, not an assumed de novo occurrence; parental genotypes are undocumented.	clinvar
PP1	Not assessed	Not assessed: no informative relatives, pedigrees, or meioses were provided; paternal origin alone is not cosegregation evidence.	clinvar
PP2	N/A	Not applicable: PP2 requires a missense variant; this nonsense change leaves nothing to evaluate for missense constraint.	generic_acmg_combination_rules
PP3	Not met	Not met: missense in-silico tools do not apply to this nonsense variant, and SpliceAI impact is low (max delta 0.019).	spliceai bayesdel
PP4	Not assessed	Not assessed: no phenotype for the tested individual was provided.	clinvar
PP5	Not met	Not met: the sole ClinVar submission is Likely pathogenic from one clinical laboratory, not an expert panel.	clinvar
BA1	Not met	Not met: allele frequency is far below any stand-alone benign population-frequency range.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: maximum observed allele frequency (8.5e-07) is far below any benign frequency threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: population data show no homozygotes and no confirmed unaffected, age-appropriate individuals.	gnomad_v4
BS3	Not assessed	Not assessed: no functional studies demonstrating normal function for this variant were available.
BS4	Not assessed	Not assessed: paternal origin does not establish whether genotype-positive relatives are clinically unaffected.	clinvar
BP1	N/A	Not applicable: BP1 concerns missense variants; this nonsense variant presents no missense change to evaluate.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented cis or trans co-occurrence with a pathogenic variant; paternal origin alone establishes neither.	clinvar PMID:25741868
BP3	N/A	Not applicable: the variant does not alter protein length within a repeat region, so BP3 does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: SpliceAI predicts no splice impact (max delta 0.019), well below the 0.2 high-recall cutoff.	spliceai
BP5	Not assessed	Not assessed: no individual phenotype, molecular diagnosis, or alternative molecular cause is provided.
BP6	Not met	Not met: no expert-panel benign assertion exists; the sole ClinVar submission is Likely pathogenic from a non-expert laboratory.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this nonsense variant alters the encoded protein sequence.	generic_acmg_combination_rules

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