Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_005475.3 | MANE Select | 5431 nt | 383–2110 |
| NM_005475.1 | Alternative | 5423 nt | 358–2085 |
| NM_005475.2 | RefSeq Select | 5425 nt | 358–2085 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -208 bp |
| Donor Loss (DL) | 0.0 | 105 bp |
| Acceptor Gain (AG) | 0.0 | -19 bp |
| Donor Gain (DG) | 0.0 | -397 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease". The evidence for this variant shows: M211V is a missense change, not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null type.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant regardless of nucleotide change". The evidence for this variant shows: there is no reported pathogenic variant with the same M211V amino acid change. Therefore, this criterion is not applied at Not Applied strength because no matching pathogenic amino acid change is known.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo data or parental testing is available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be confirmed.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been assayed.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case–control or affected‐individual data are available. Therefore, this criterion is not applied at Not Applied strength because there is no prevalence data in affected cohorts.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no information on a mutational hotspot or characterized functional domain at residue 211. Therefore, this criterion is not applied at Not Applied strength because domain/hotspot annotation is lacking.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: extremely rare in population databases (gnomAD MAF=0.00186%, no homozygotes). Therefore, this criterion is applied at Moderate strength because the variant meets the rarity threshold.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on zygosity or phase with another variant. Therefore, this criterion is not applied at Not Applied strength because trans phasing information is not available.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a missense substitution with no change in length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense changes reported at residue M211. Therefore, this criterion is not applied at Not Applied strength because no precedent pathogenic variant exists at this site.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no family testing or de novo assumption data. Therefore, this criterion is not applied at Not Applied strength because de novo status is not established.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation or family data. Therefore, this criterion is not applied at Not Applied strength because segregation evidence is lacking.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: gene‐level missense constraint or disease mechanism data are not available. Therefore, this criterion is not applied at Not Applied strength because gene-level missense tolerance is unknown.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational tools (REVEL=0.03, CADD, SIFT, PolyPhen-2, etc.) predict benign impact and no splicing effect. Therefore, this criterion is not applied at Not Applied strength because predictions do not support deleteriousness.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no clinical phenotype or family history information is provided. Therefore, this criterion is not applied at Not Applied strength because phenotype data are missing.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar classifies it as VUS in two laboratories. Therefore, this criterion is not applied at Not Applied strength because no reputable pathogenic assertion exists.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (>5%)". The evidence for this variant shows: MAF=0.00186%, far below the BA1 threshold. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not high enough.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: frequency is extremely low (0.00186%), below expected thresholds. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed expected.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: no information on healthy adult carriers with confirmed penetrance. Therefore, this criterion is not applied at Not Applied strength because healthy carrier data are unavailable.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional assays have been conducted. Therefore, this criterion is not applied at Not Applied strength because functional studies are absent.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is not available.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: the disease mechanism for SH2B3 is not established as exclusively LoF. Therefore, this criterion is not applied at Not Applied strength because mechanism data are insufficient.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". The evidence for this variant shows: no data on co-occurrence or phasing with other variants. Therefore, this criterion is not applied at Not Applied strength because variant phasing is unknown.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a single‐nucleotide missense substitution, not an in‐frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant type does not match.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: REVEL score 0.03, CADD, SIFT, PolyPhen-2, MutationAssessor, PROVEAN, MetaSVM, MetaLR, DEOGEN2 all predict benign, and SpliceAI shows no splice alteration. Therefore, this criterion is applied at Supporting strength because computational predictions consistently indicate benign impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no reports of the variant co-occurring with an alternative molecular cause. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no reputable benign assertions (ClinVar reports VUS). Therefore, this criterion is not applied at Not Applied strength because no benign assertion exists.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense substitution, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.