LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_004004.6:c.445G>A
GJB2
· NP_003995.2:p.(Ala149Thr)
· NM_004004.6
GRCh37: chr13:20763276 C>T
·
GRCh38: chr13:20189137 C>T
Gene:
GJB2
Transcript:
NM_004004.6
Final call
VUS
BP4 supporting
Variant details
Gene
GJB2
Transcript
NM_004004.6
Protein
NP_003995.2:p.(Ala149Thr)
gnomAD AF
5.204525458803703e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP4 (Supporting): SpliceAI predicts no impact on splicing (max delta 0.00), meeting the VCEP's no-splicing-impact clause.
2
VUS: with only BP4 (Supporting) applied and no pathogenic criteria met, the variant is classified as a variant of uncertain significance under the ACMG/AMP 2015 fallback.
Final determination:
1 BP(Supporting) alone does not reach any Pathogenic/LP/Benign/LB threshold under generic ACMG 2015 rules → 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 | N/A | Not applicable: missense substitution, so no null-variant mechanism (nonsense-mediated decay, truncation, splice disruption) applies. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PS1 | Not assessed | Not assessed: no established pathogenic variant producing the identical p.Ala149Thr change via a different nucleotide was identified. |
clinvar
|
| PS2 | Not assessed | Not assessed: no confirmed or assumed de novo occurrence was documented for this variant. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| PS3 | Not assessed | Not assessed: no functional assay of p.Ala149Thr was found in the four full-text papers reviewed. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| PS4 | Not assessed | Not assessed: no eligible case-control comparison or qualifying proband count was available. |
cspec
PMID:10982180
PMID:15146474
PMID:23073770
|
| PM1 | Not assessed | Not assessed: the VCEP PM1 rule covers only KCNQ4 amino acids 271-292; no GJB2 hotspot rule applies. |
cspec
PMID:10982180
PMID:23073770
|
| PM2 | Not met | Not met: gnomAD v4.1 Middle Eastern allele frequency 0.000329 exceeds the 0.00007 (0.007%) PM2 threshold. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| PM3 | Not assessed | Not assessed: no reliable confirmation that the variant lies in trans with a pathogenic allele was available. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| PM4 | N/A | Not applicable: missense substitution causes no change in protein length. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PM5 | Not assessed | Not assessed: no alternate established pathogenic missense change at codon 149 was available as a comparator. |
pm5_candidates
cspec
|
| PM6 | Not assessed | Not assessed: parental testing and inheritance data were insufficient to infer a de novo event. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| PP1 | Not assessed | Not assessed: no validated segregation of this variant through affected relatives was reported. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| PP2 | N/A | Not applicable: the Hearing Loss VCEP marks PP2 as not applicable for GJB2. |
cspec
|
| PP3 | Not met | Not met: REVEL 0.499 is below the >=0.7 PP3 threshold. |
cspec
revel
spliceai
|
| PP4 | Not assessed | Not assessed: no phenotype data or evidence of full relevant-gene-set sequencing was available. |
cspec
|
| PP5 | N/A | Not applicable: no expert-panel ClinVar submission supports PP5. |
cspec
clinvar
|
| BA1 | Not met | Not met: the highest observed allele frequency (0.000329, Middle Eastern) is far below the 0.005 BA1 threshold. |
cspec
gnomad_v4
gnomad_v2
|
| BS1 | Not met | Not met: the highest allele frequency (0.000329) is below even the 0.0007 supporting BS1 threshold. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS2 | Not met | Not met: no homozygotes or biallelic control observations were documented for this variant. |
cspec
gnomad_v4
gnomad_v2
PMID:15146474
|
| BS3 | Not assessed | Not assessed: no assay showed p.Ala149Thr function comparable to wildtype. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| BS4 | Not assessed | Not assessed: no validated genotype/phenotype-discordant family member was documented. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| BP1 | N/A | Not applicable: the Hearing Loss VCEP marks BP1 as not applicable for GJB2. |
cspec
|
| BP2 | Not met | Not met: no confirmed cis configuration with a pathogenic variant or trans with a dominant variant was documented. |
cspec
PMID:10982180
PMID:15146474
PMID:16300957
PMID:23073770
|
| BP3 | N/A | Not applicable: missense substitution, not an in-frame indel in a repetitive region. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| BP4 | Met | Met (Supporting): SpliceAI predicts no splicing impact (max delta 0.00), satisfying BP4's no-impact clause. Flagged for human review: MaxEntScan was not available, so SpliceAI was used for the BP4 splicing sub-path. |
cspec
revel
spliceai
|
| BP5 | N/A | Not applicable: BP5 must not be used for autosomal-recessive disease, where carriers may have an alternate cause. |
cspec
|
| BP6 | N/A | Not applicable: no benign/likely-benign expert-panel ClinVar classification exists for this variant. |
cspec
clinvar
|
| BP7 | N/A | Not applicable: missense substitution, not a synonymous variant. |
generic_acmg_combination_rules
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.