MET c.2419-21G>C, p.?
NM_001127500.3:c.2419-21G>C
COSMIC ID: COSN31986947
Variant of Uncertain Significance (VUS)
NM_001127500.3:c.2419-21G>C is an intronic variant in MET with no demonstrated functional impact, mixed computational predictions, and a population frequency of 0.211%. Only BP6 (Supporting) was applied based on a reputable source reporting likely benign. Insufficient evidence exists to classify this variant as benign or pathogenic, resulting in a VUS.
ACMG/AMP Criteria Applied
BP6
Genetic Information
Gene & Transcript Details
Gene
MET
Transcript
NM_001127500.2
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001127500.3 | Alternative | 21 exons | Forward |
| NM_001127500.1 | Alternative | 21 exons | Forward |
Variant Details
HGVS Notation
NM_001127500.3:c.2419-21G>C
Protein Change
?
Location
Exon 10
(Exon 10 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN31986947
Variant interpretation based on transcript NM_001127500.2
Genome Browser
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HGVS InputNM_001127500:c.2419-21G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.211%
Common
Highest in Population
European (non-Finnish)
0.409%
Common
Global: 0.211%
European (non-Finnish): 0.409%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 279790Alt: 590Homozygotes: 2
ACMG Criteria Applied
None
This variant is present in gnomAD (MAF= 0.211%, 590/279790 alleles, homozygotes = 2) and at a higher frequency in the European (non-Finnish) population (MAF= 0.409%, 523/127876 alleles, homozygotes = 2). The variant frequency does not support application of PM2, BA1, or BS1 criteria.
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.87
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
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 (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion)'. The evidence for this variant shows: NM_001127500.3:c.2419-21G>C is an intronic variant at position -21 from the exon, not affecting canonical splice sites and not a null variant. Therefore, this criterion is not applied because the variant does not meet the rule requirements.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: the protein change is unknown. Therefore, this criterion is not applied because the variant does not result in a known amino acid substitution matching a pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
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: there are no data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
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 because functional impact has not been demonstrated.
PS4
PS4 (Not Applied) Strength Modified
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 prevalence data in affected individuals. Therefore, this criterion is not applied due to absence of statistical association data.
PM1
PM1 (Not Applied) Strength Modified
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: it is an intronic variant outside any characterized functional domain or mutational hotspot. Therefore, this criterion is not applied because the variant is not located in a known hotspot or functional domain.
PM2
PM2 (Not Applied) Strength Modified
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: present in gnomAD at MAF=0.211% (590/279,790 alleles) with homozygotes observed. Therefore, this criterion is not applied because the variant is not absent or extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
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 phasing with pathogenic variants. Therefore, this criterion is not applied due to lack of allelic configuration data.
PM4
PM4 (Not Applied) Strength Modified
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: the protein consequence is unknown and there is no evidence of in-frame indel or stop-loss. Therefore, this criterion is not applied because it does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
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: protein change is unknown and no known pathogenic missense at the same residue. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
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 data on de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
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 family segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
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: it is an intronic variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows: in silico predictions are mixed—with a low CADD score (0.87) suggesting benign effect and inconclusive SpliceAI. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's 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 provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
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 reports likely benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: MAF is 0.211%, well below the 5% threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF is 0.211% with unknown disorder prevalence. Therefore, this criterion is not applied due to insufficient frequency threshold data.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: two homozygotes are reported in gnomAD but health status is not documented. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
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 studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
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: it is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no data on allelic phase with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
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 change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: in silico results are mixed, with no consensus benign prediction. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
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 case reports linking this variant to disease in the context of another molecular diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
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: ClinVar lists this variant as Likely benign by two clinical laboratories without accessible primary data. Therefore, this criterion is applied at Supporting strength because a reputable source reports benign status without available evidence.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: this is an intronic variant, not synonymous. Therefore, this criterion is not applied.