Classification rationale

PM2 VUS

SH2B3 c.*2C>T

The SH2B3 c.*2C>T (NP_005466.1:p.?) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the usual PM2 threshold of 0.001 (0.1%).² Although SH2B3 loss of function is an established disease mechanism, this variant is a 3'UTR substitution rather than a nonsense, frameshift, or canonical splice variant, so generic PVS1 criteria do not apply.³ In silico splice prediction does not support a splice-altering effect, with a SpliceAI maximum delta score of 0.04.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

4 spliceai ↗

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.

Gene diagram · NM_005475.2 · variants mapped to exon structure

SH2B3 NM_005475.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from population databases reviewed. It was not observed in gnomAD v2.1 or gnomAD v4.1, which is below the usual PM2 rarity threshold of less than 0.001 (0.1%), supporting PM2.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 5 not met · 14 not assessed

Pathogenic

PS2 No confirmed de novo data with verified maternity and paternity were identified for this variant, so PS2 was not assessed.

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.

PS4 This variant has not been reported in ClinVar, and no case-control or enrichment data showing increased prevalence in affected individuals were identified, so PS4 is not met.

PM1 No established mutational hotspot or well-characterized critical functional region supporting PM1 at this 3'UTR position was identified.

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder, so PM3 was not assessed.

PM6 No assumed de novo occurrence data were identified for this variant, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP3 Available computational evidence does not support a damaging splice effect.

PP4 No phenotype-specific evidence was identified showing a clinical presentation highly specific for a disorder caused by this variant, so PP4 was not assessed.

PP5 No pathogenic assertion from a reputable source was identified for this variant, so PP5 was not assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is below the BA1 threshold of 0.01 (1%) and BA1 is not met.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is below the BS1 threshold of 0.003 (0.3%) and BS1 is not met.

BS2 No direct evidence was identified showing this variant in healthy adult individuals in a context appropriate for BS2, so BS2 was not assessed.

BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not assessed.

BS4 No family studies showing lack of cosegregation with disease were identified for this variant, so BS4 was not assessed.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a relevant setting, so BP2 was not assessed.

BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, but this isolated splice prediction does not fully establish a benign effect for a 3'UTR regulatory variant.

BP5 No alternate molecular explanation for the reported phenotype was identified from the available evidence, so BP5 was not assessed.

BP6 No benign assertion from a reputable source was identified for this variant, so BP6 was not assessed.

N/A · 8 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · 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.

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 v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional No data

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

OncoKB ↗

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Sources & reference links

5Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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