Variant classification summary

NM_014915.2:c.-140C>G

ANKRD26 · NP_055730.2:p.? · NM_014915.2

GRCh37: chr10:27389395 G>C · GRCh38: chr10:27100466 G>C

Gene: ANKRD26 Transcript: NM_014915.2

Final call

Benign

BA1_stand-alone_benign BS1_Strong

Variant details

Gene

ANKRD26

Transcript

NM_014915.2

Protein

NP_055730.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ANKRD26 c.-140C>G (NP_055730.2:p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Benign.

2

This variant is common in population databases, with allele frequencies of 0.0640054 (6.40054%) in gnomAD v2.1 and 0.0478907 (4.78907%) in gnomAD v4.1, which are well above benign thresholds.

3

In silico splice prediction does not support a splice-altering effect, with a SpliceAI maximum delta score of 0.07.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	Although ANKRD26 has germline loss-of-function disease relevance, this 5'UTR substitution does not fall into the generic PVS1 null-variant categories such as nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is not applicable because this variant is in the 5'UTR and does not create the same amino acid change as a previously established pathogenic variant.
PS2	Not assessed	No confirmed de novo data with verified maternity and paternity were identified, so PS2 cannot be assessed.
PS3	Not assessed	No validated functional studies demonstrating a damaging effect of this specific variant were identified from the available evidence, so PS3 was not assessed.
PS4	Not met	This variant has not been observed in COSMIC and is listed in ClinVar as Benign; no case-control or enrichment data showing increased prevalence in affected individuals were identified, so PS4 is not met.	clinvar
PM1	Not assessed	No established mutational hotspot or well-characterized critical functional region for applying PM1 to this specific 5'UTR position was identified in the available evidence.
PM2	Not met	This variant is common in population databases rather than absent or rare. In gnomAD v2.1 the allele frequency is 0.0640054 (6.40054%), and in gnomAD v4.1 the allele frequency is 0.0478907 (4.78907%), both far above the usual rarity threshold of less than 0.001 for PM2, so PM2 is not met.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder, so PM3 was not assessed.
PM4	N/A	PM4 is not applicable because this variant does not change protein length and is located in the 5'UTR.
PM5	N/A	PM5 is not applicable because this variant is in the 5'UTR and does not alter an amino acid residue where a different pathogenic missense change has been established.
PM6	Not assessed	No assumed de novo occurrence data were identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified, so PP1 was not assessed.
PP2	N/A	PP2 is not applicable because this is not a missense variant.
PP3	Not met	Available computational evidence does not support a damaging effect on splicing. SpliceAI shows a maximum delta score of 0.07, which is below commonly used concern thresholds, so PP3 is not met.	spliceai
PP4	Not assessed	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	Not assessed	Although ClinVar lists this variant as Benign, PP5 was not used because this criterion concerns pathogenic assertions from a reputable source and independent evidence is available.	clinvar
BA1	Met	This variant is far above the benign stand-alone population threshold. The allele frequency is 0.0640054 (6.40054%) in gnomAD v2.1 and 0.0478907 (4.78907%) in gnomAD v4.1, both above the BA1 threshold of 0.01 (1%), supporting BA1.	gnomad_v2 gnomad_v4
BS1	Met	The population frequency is also well above the strong benign threshold. The allele frequency is 0.0640054 in gnomAD v2.1 and 0.0478907 in gnomAD v4.1, both above the BS1 threshold of 0.003 (0.3%), so BS1 is met.	gnomad_v2 gnomad_v4
BS2	Not assessed	Population databases show many homozygotes, but no direct evidence was identified confirming unaffected status in a setting appropriate for BS2, so this criterion was not assessed.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of this specific variant were formally curated in the available evidence for BS3 application.
BS4	Not assessed	No segregation studies showing lack of cosegregation with disease were identified, so BS4 was not assessed.
BP1	N/A	BP1 is not applicable because this is not a missense variant.
BP2	Not assessed	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 any relevant setting, so BP2 was not assessed.
BP3	N/A	BP3 is not applicable because this is not an in-frame insertion or deletion in a repetitive region.
BP4	Not met	SpliceAI predicts no significant splice impact, with a maximum delta score of 0.07, but this isolated splice prediction does not fully establish a benign effect for a 5'UTR regulatory variant. Therefore BP4 is not met.	spliceai
BP5	Not assessed	No alternate molecular explanation for the reported phenotype was identified from the available evidence, so BP5 was not assessed.
BP6	Not assessed	ClinVar reports this variant as Benign, but BP6 was not used because the submission is not from an expert panel and strong independent benign population evidence is already available.	clinvar
BP7	N/A	BP7 is not applicable because this variant is not a synonymous or intronic change outside splice regions; it is a 5'UTR substitution.

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