ATM c.2466+1G>T, p.Splice_Site
NM_000051.4:c.2466+1G>T
Pathogenic
c.2466+1G>T is a canonical splice donor site variant in ATM predicted to abolish normal splicing (PVS1_VS), absent from controls (PM2_Supporting), and supported by high-impact SpliceAI in silico evidence (PP3_Supporting). These criteria together support a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS1
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
ATM
Transcript
NM_000051.4
MANE Select
Total Exons
63
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 63 exons | Forward |
Variant Details
HGVS Notation
NM_000051.4:c.2466+1G>T
Protein Change
Splice
Location
Exon 16
(Exon 16 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.2466+1G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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: 5.98
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength." The variant is a +1 splice donor site change (c.2466+1G>T) predicted to abolish normal splicing in ATM, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because +1/2 splice variants meeting PVS1 decision tree cause null effect.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Strong Use for protein changes as long as splicing is ruled-out for both alterations..." The variant is a splice site alteration, not a missense change, so PS1 does not apply.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS2 applies to de novo observations with confirmed maternity and paternity. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: PS3 requires functional studies showing a deleterious effect on ATM-specific features. No functional characterization exists for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS4 requires case-control data with significant association. No such data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM1 applies to variants in well‐established functional domains without benign variation. This splice site does not map to a specific protein domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "PM2 Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation..." The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because it is extremely rare or absent in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies to variants observed in trans with a pathogenic variant in a recessive disorder. No trans or zygosity data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM4 applies to protein length changes. This is a splicing variant, not an in‐frame indel or stop-loss. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: PM5_supporting for premature termination codons upstream of p.Arg3047 with NMD, requiring observed high-quality splicing data. Only in silico predictions exist. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM6 applies to assumed de novo without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP1 requires segregation data in affected family members. No segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP2 applies to missense in a gene with low rate of benign missense. This is a splice variant. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: "PP3 Supporting Strength: ...RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing." SpliceAI predicts donor loss (0.95). Therefore, PP3 is applied at Supporting strength because in silico tools support a deleterious splice effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP4 requires a highly specific phenotype. No phenotype or family history details are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP5 applies to variants reported as pathogenic by reputable sources. This variant is not in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BA1 requires allele frequency >5%. The variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS1 requires allele frequency >0.05%. The variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS2 applies when variant observed in healthy adult controls. No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 requires functional studies showing no impact on ATM function. No benign functional data exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS4 requires lack of segregation in affected members. No segregation data are provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP1 applies to missense in a gene where only LOF causes disease. This is a splice variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: BP2 applies to cis observations with pathogenic variants. No phasing data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP3 applies to in-frame indels in repetitive regions. Not applicable for a splice variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: BP4 applies when in silico predictors show no impact. SpliceAI predicts high impact. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP5 applies when variant found in trans or cis with another pathogenic variant causing the phenotype. No such data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP6 applies to reputable source reporting as benign. No such report exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP7 applies to synonymous or deep intronic variants >+7/−40. This is a canonical splice donor variant. Therefore, BP7 is not applied.