Variant classification summary

NM_000222.2:c.1990+8C>T

KIT · NP_000213.1:p.? · NM_000222.2

GRCh37: chr4:55594295 C>T · GRCh38: chr4:54728129 C>T

Gene: KIT Transcript: NM_000222.2

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign

Variant details

Gene

KIT

Transcript

NM_000222.2

Protein

NP_000213.1:p.?

gnomAD AF

1.7783287774243704e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000222.2:c.1990+8C>T is an intronic variant at position +8 in intron 13 of KIT, classified as Likely benign based on the generic ACMG/AMP 2015 framework (PMID:25741868).

2

SpliceAI predicts no significant splicing impact (max delta score=0.02), meeting BP4 at supporting benign level.

3

The variant is classified as Likely benign in ClinVar (VC ID 415791) by Labcorp Genetics/Invitae, meeting BP6 at supporting benign level.

4

The variant is present at extremely low frequency in gnomAD (v2.1 AF=0.00279%, v4.1 AF=0.00178%), meeting PM2 at supporting pathogenic level.

5

With two supporting benign criteria (BP4, BP6) and one supporting pathogenic criterion (PM2), the net evidence meets the generic ACMG/AMP threshold for Likely benign (≥2 supporting benign criteria).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting 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	NM_000222.2:c.1990+8C>T is an intronic variant at position +8, not a canonical ±1,2 splice site variant. Per ClinGen SVI PVS1 framework (PMC6185798), this variant does not fall into any null-variant bucket and is not eligible for PVS1 assessment.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires a same amino acid change from a different nucleotide change. This is an intronic variant with no amino acid change, therefore PS1 does not apply.
PS2	Not assessed	No de novo data with confirmed maternity and paternity were identified in ClinVar submissions or the literature for this variant.
PS3	Not assessed	No well-established functional studies were identified for this variant. The single paper retrieved for functional theme (PMID:23852704) is a tumor marker guideline and does not mention this variant.
PS4	Not assessed	No case-control or cohort data demonstrating enrichment of this variant in affected individuals were identified. Literature-tagged papers (PMID:22685257, 23852704, 25394175, 28492532) are general guidelines/reviews that do not mention this specific variant.
PS5	N/A	PS5 requires a reputable source reporting the variant as pathogenic. The only ClinVar submission classifies this variant as Likely benign, not pathogenic. No other source reports it as pathogenic.	clinvar
PM1	N/A	PM1 applies to variants located in a mutational hot spot or critical functional domain. NM_000222.2:c.1990+8C>T is an intronic variant at +8 in intron 13, not located in a coding functional domain or recognized mutational hot spot.
PM2	Met	This variant is present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00279%, v4.1 AF=0.00178%), well below the 0.1% non-VCEP PM2 threshold. One homozygote is observed in each gnomAD version (South Asian subpopulation), which is noted but does not disqualify PM2 at this allele frequency.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different missense change at the same residue previously established as pathogenic. This is an intronic variant with no protein residue; same-residue missense comparator semantics cannot be applied.	pm5_candidates
PM6	Not assessed	PM6 requires a de novo observation without confirmation of maternity and paternity. No de novo data were identified in ClinVar submissions or the literature for this variant.
PP1	Not assessed	No cosegregation data in affected families were identified for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is an intronic variant, not a missense change.
PP3	Not met	Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splicing impact (max delta=0.02). REVEL and BayesDel scores are not available for this intronic variant, and HCI prior does not cover KIT.	spliceai
PP4	Not assessed	No patient phenotype or family history data were provided for this variant. Cannot assess whether the clinical presentation is highly specific for a KIT-related disorder.
PP5	Not met	PP5 requires a reputable source reporting the variant as pathogenic. ClinVar reports this variant as Likely benign (1 clinical laboratory, criteria provided single submitter, VC ID 415791). No reputable source reports it as pathogenic.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in any population. The highest subpopulation frequency is 0.00886% in South Asian (gnomAD v4.1), far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 threshold for non-VCEP is AF >0.3%. The variant allele frequency in gnomAD is 0.00279% (v2.1) and 0.00178% (v4.1), well below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	A homozygous individual is observed in gnomAD (South Asian subpopulation), which is notable for an autosomal dominant KIT-related disorder. However, gnomAD is a general population database and does not confirm the individual is a healthy adult with full expected penetrance. Without phenotype confirmation, BS2 cannot be reliably applied or excluded.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect were identified for this variant. The SpliceAI delta score of 0.02 suggests no splicing impact but does not alone constitute a well-established functional study. The literature-tagged functional paper (PMID:23852704) does not mention this variant.	spliceai
BS4	Not assessed	No segregation data in affected families are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_000222.2:c.1990+8C>T is an intronic variant, not a missense change.
BP2	Not assessed	No data on cis/trans phasing with pathogenic variants are available for this variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single nucleotide substitution, not an in-frame indel.
BP4	Met	SpliceAI predicts no significant splicing impact for this intronic variant (max delta score=0.02). While REVEL and BayesDel are unavailable for intronic variants, SpliceAI is the primary relevant in silico tool for splice region variants and supports a benign interpretation.	spliceai
BP5	Not assessed	BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such data are available for this variant.
BP6	Met	This variant is classified as Likely benign in ClinVar (VC ID 415791) by a clinical testing laboratory (Labcorp Genetics/Invitae), which constitutes a reputable source reporting the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact and non-conserved nucleotide. NM_000222.2:c.1990+8C>T is an intronic variant, not a synonymous coding change.
PM3	N/A	Skipped per instruction: PM3 applies to recessive disorders and requires observation in trans with a pathogenic variant.
PM4	N/A	Skipped per instruction: PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This is a single nucleotide substitution.

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