Classification rationale

PM2 VUS

SMO c.1886G>C

NM_005631.4:c.1886G>C (p.Arg629Thr) in SMO is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.¹ No additional pathogenic or benign criteria were met. With only one supporting pathogenic criterion (PM2_supporting) and zero benign criteria, the variant is classified as a Variant of Uncertain Significance (VUS) per the ACMG/AMP 2015 guidelines (PMID:25741868).²

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 generic_acmg_combination_rules

Gene diagram · NM_005631.4 · variants mapped to exon structure

SMO NM_005631.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_005631.4:c.1886G>C (p.Arg629Thr) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength (allele frequency <0.1% in all population cohorts).

Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No previously established pathogenic variant with the same amino acid change (p.Arg629Thr) has been reported in ClinVar, COSMIC, or the literature.

PS2 No de novo observation with confirmed paternity and maternity is available for this variant.

PS3 No well-established in vitro or in vivo functional studies supportive of a damaging effect were identified for NM_005631.4:c.1886G>C.

PS4 No case-control or cohort data demonstrating significantly increased prevalence of this variant in affected individuals versus controls.

PM1 The variant does not lie in a statistically significant mutational hotspot, and no CSPEC/VCEP-defined critical functional domain has been established for SMO.

PM6 No assumed de novo observation (without confirmation of paternity and maternity) is available for this variant.

PP1 No co-segregation data in multiple affected family members is available for this variant.

PP2 SMO is not included in the HCI prior gene list; no gene-specific missense constraint metric is available to support a low rate of benign missense variation.

PP3 Computational evidence is mixed: REVEL score of 0.897 supports a deleterious effect, but BayesDel noAF score of 0.292 does not reach a confidently pathogenic threshold, and SpliceAI predicts no splice impact (max delta = 0.00).

PP4 No patient phenotype or family history data specific to a disease with a single genetic etiology are available for assessment.

PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic.

Benign

BA1 The variant is absent from gnomAD; allele frequency does not exceed 5%.

BS1 The variant is absent from gnomAD; allele frequency does not exceed the expected threshold for the disorder (>0.3% for non-VCEP).

BS2 No observation of this variant in healthy adult individuals has been reported; the variant is absent from gnomAD.

BS3 No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing are available for this variant.

BS4 No segregation data are available to assess lack of segregation with disease in affected family members.

BP1 SMO is a proto-oncogene in the hedgehog signaling pathway; somatic activating missense variants are well-established in basal cell carcinoma and medulloblastoma.

BP2 No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.

BP4 Computational evidence does not uniformly suggest no impact: REVEL score of 0.897 predicts a deleterious effect, which contradicts a benign computational consensus.

BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported.

BP6 This variant is absent from ClinVar; no reputable source has reported it as benign.

N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

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

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.897. BayesDel score = 0.291989.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMO, a G-protein coupled receptor, is mutated in various cancers including basal cell carcinoma and medulloblastoma.

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

Re-run this variant?