NM_017763.5:c.252+2C>G

RNF43 · NP_060233.3:p.? · NM_017763.5

GRCh37: chr17:56492685 G>C · GRCh38: chr17:58415324 G>C

Gene: RNF43 Transcript: NM_017763.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

RNF43

Transcript

NM_017763.5

Protein

NP_060233.3:p.?

gnomAD AF

6.19622451647762e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_017763.5:c.252+2C>G is a canonical splice donor variant at the +2 position of intron 2 in RNF43, a gene where loss of function is an established mechanism for germline disease including serrated polyposis syndrome and colorectal cancer predisposition. Assessed under ClinGen SVI PVS1 recommendations (PMC6185798) as a null variant (PVS1).

The variant is extremely rare in population databases, with an allele frequency of 3.98e-06 in gnomAD v2.1 (1/251,184 alleles, 0 homozygotes) and 6.20e-07 in gnomAD v4.1 (1/1,613,886 alleles, 0 homozygotes), and is absent from gnomAD-Canada. Allele frequency is well below the 0.1% PM2 threshold (PM2).

ClinVar reports this variant as Uncertain significance (2 clinical laboratories, criteria provided, single submitter; Variation ID 3669600). No variant-specific functional studies, segregation data, or de novo observations were identified in the reviewed literature.

SpliceAI predicts no significant splice impact (max delta = 0.0), which conflicts with the canonical splice site expectation. This discrepancy may reflect SpliceAI calibration for a non-canonical reference donor (C at +2 instead of the consensus T). RNA functional studies are recommended to resolve this conflict.

Under ACMG/AMP 2015 generic classification rules, 1 Very Strong (PVS1) + 1 Moderate (PM2) supports a classification of Likely Pathogenic. However, the SpliceAI conflict warrants caution and human review.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	NM_017763.5:c.252+2C>G is a canonical splice donor variant at the +2 position of intron 2 in RNF43, a gene where loss of function is an established germline disease mechanism (serrated polyposis syndrome, colorectal cancer predisposition). Assessed under ClinGen SVI PVS1 recommendations (PMC6185798) as a null variant in a gene with confirmed LOF disease mechanism. SpliceAI predicts no significant splice impact (max delta = 0.0), which conflicts with the canonical splice site expectation; RNA functional studies are recommended to confirm the splicing effect.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Splice variant does not result in an amino acid substitution; same amino acid change from a different nucleotide change is not applicable.
PS2	Not assessed	No de novo observation data available for this variant in any reviewed source.
PS3	Not assessed	No variant-specific functional studies identified. The ClinVar-submitted PMIDs (17576681, 9536098) are general splicing methodology papers that do not mention NM_017763.5:c.252+2C>G.
PS4	Not assessed	No case-control or prevalence data comparing affected individuals to controls available for this variant.
PS5	N/A	Not a missense variant; same-residue pathogenic comparator evaluation is not applicable for a splice variant.
PM1	N/A	Splice variant located in intron 2, outside coding sequence. No mutational hotspot or critical functional domain directly affected by an amino acid substitution at this position.
PM2	Met	Extremely rare in population databases. gnomAD v2.1 allele frequency = 3.98e-06 (1/251,184 alleles, 0 homozygotes). gnomAD v4.1 allele frequency = 6.20e-07 (1/1,613,886 alleles, 0 homozygotes). Absent from gnomAD-Canada. Allele frequency is well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No residue context for same-position comparator evaluation; splice variant does not produce a defined amino acid change for residue-level comparison.
PM6	Not assessed	No de novo observation data available for this variant.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	N/A	Splice variant, not a missense change; PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	SpliceAI max delta = 0.0 (no significant splice impact predicted). BayesDel score = 0.65 (equivocal). Additionally, per PMC6185798 guidance, PP3 should not be stacked with PVS1 for the same splice-effect prediction evidence when PVS1 is applied for a canonical splice variant.	spliceai bayesdel
PP4	Not assessed	No phenotype specificity data available for affected individuals carrying this variant.
PP5	Not met	ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter). The variant has not been reported as pathogenic or likely pathogenic by a reputable source.	clinvar
BA1	Not met	gnomAD allele frequency (v2.1: 3.98e-06; v4.1: 6.20e-07) is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (v2.1: 3.98e-06; v4.1: 6.20e-07) is far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation in healthy adults available.
BS3	Not assessed	No variant-specific functional studies demonstrating no deleterious effect were identified.
BS4	Not assessed	No non-segregation data available for this variant.
BP1	N/A	Splice variant, not a missense change; BP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism.
BP2	Not assessed	No data on observation in trans with a pathogenic variant available.
BP4	Not met	SpliceAI predicts no splice impact (max delta = 0.0), but this is insufficient to support a benign interpretation given the canonical splice site position. SpliceAI may not be well-calibrated for non-canonical reference donor sequences. BayesDel score of 0.65 is equivocal. Multiple lines of in silico evidence do not convincingly predict a benign effect.	spliceai bayesdel
BP5	Not assessed	No data on alternate molecular basis for disease in cases carrying this variant.
BP6	Not met	ClinVar reports Uncertain significance, not benign or likely benign. BP6 requires classification as benign by a reputable source.	clinvar
BP7	N/A	Not a synonymous variant; c.252+2C>G is an intronic splice donor variant. BP7 applies to synonymous variants with no predicted splice effect.
BP3	N/A	Splice variant does not produce an in-frame insertion/deletion; BP3 applies to in-frame indels in repetitive regions without known function.
PM3	N/A	No recessive inheritance context established; PM3 requires observation in trans with a pathogenic variant for recessive disorders.
PM4	N/A	Splice variant does not alter protein length via non-repeat in-frame indel; PM4 applies to non-repeat in-frame insertions/deletions or stop-loss variants.

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