SRSF2 c.155A>C, p.Lys52Thr
NM_003016.4:c.155A>C
Variant of Uncertain Significance (VUS)
The SRSF2 K52T variant is absent from population databases (PM2) but lacks sufficient pathogenic evidence; computational predictions favor benign effect (BP4). No additional criteria support pathogenicity or benignity, resulting in classification as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
SRSF2
Transcript
NM_003016.5
Total Exons
2
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_003016.4 | Alternative | 2 exons | Reverse |
| NM_003016.2 | Alternative | 2 exons | Reverse |
| NM_003016.3 | Alternative | 2 exons | Reverse |
Variant Details
HGVS Notation
NM_003016.4:c.155A>C
Protein Change
K52T
Location
Exon 1
(Exon 1 of 2)
5'Exon Structure (2 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 52 in gene SRSF2
Variant interpretation based on transcript NM_003016.5
Genome Browser
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HGVS InputNM_003016:c.155A>C
Active Tracks
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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
No evidence of other pathogenic variants at position 52 in gene SRSF2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.591
0.591
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 5.39
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 (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease'. The evidence for this variant shows: It is a missense change (K52T), not a null variant. Therefore, this criterion is not applied at any strength because the variant type does not meet the null variant requirement.
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: No previously established pathogenic variant with the same K52 amino acid change. Therefore, this criterion is not applied at any strength because there is no matching known 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: No information on parental testing or de novo occurrence. Therefore, this criterion is not applied at any strength because de novo status cannot be confirmed.
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 for SRSF2 K52T. Therefore, this criterion is not applied at any strength because functional evidence is lacking.
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 cohort data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at any strength because no prevalence data are available.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or well‐established functional domain without benign variation'. The evidence for this variant shows: K52 is not within a known mutational hotspot or critical functional domain for SRSF2 (hotspot is at codon 95). Therefore, this criterion is not applied at any strength.
PM2
PM2 (Moderate)
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: Variant not found in gnomAD, ExAC, 1000 Genomes, or ESP. Therefore, this criterion is applied at Moderate strength because the variant is absent from 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: SRSF2‐related disease is not recessive and no trans data are available. Therefore, this criterion is not applied at any strength.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: It is a single amino acid substitution without change to protein length. Therefore, this criterion is not applied at any strength.
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 missense change determined to be pathogenic has been seen before'. The evidence for this variant shows: No other pathogenic missense variants reported at codon K52. Therefore, this criterion is not applied at any strength.
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 at any strength.
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 segregation data available. Therefore, this criterion is not applied at any strength.
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: SRSF2 has known pathogenic missense hotspot at codon 95, but the overall gene has multiple benign and uncertain missense variants; K52 is not a common site. Therefore, this criterion is not applied at any strength.
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'. The evidence for this variant shows: In silico predictions are mixed (REVEL 0.59, CADD 5.39, SpliceAI 0). Therefore, this criterion is not applied at any strength because computational evidence is conflicting.
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 detailed phenotype or family history provided. Therefore, this criterion is not applied at any strength.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without available evidence'. The evidence for this variant shows: Not reported in ClinVar or other databases. Therefore, this criterion is not applied at any strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is greater than 5% in population databases'. The evidence for this variant shows: Absent from population databases. Therefore, this criterion is not applied at any strength.
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: Absent from population. Therefore, this criterion is not applied at any strength.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: No data on occurrence in healthy individuals. Therefore, this criterion is not applied at any strength.
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 available. Therefore, this criterion is not applied at any strength.
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. Therefore, this criterion is not applied at any strength.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss-of-function causes disease'. The evidence for this variant shows: SRSF2 disease mechanism is gain-of-function missense at hotspot P95, not strict LoF. Therefore, this criterion is not applied at any strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant'. The evidence for this variant shows: No phasing data. Therefore, this criterion is not applied at any strength.
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 a known function'. The evidence for this variant shows: It is a single amino acid substitution. Therefore, this criterion is not applied at any strength.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: SpliceAI predicts no impact on splicing (score 0), CADD score is 5.39, and REVEL is 0.59 with mixed interpretation. Overall computational evidence suggests no functional impact. Therefore, this criterion is applied at Supporting strength because computational tools do not support a deleterious effect.
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 with an alternate molecular cause. Therefore, this criterion is not applied at any strength.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without accessible evidence'. The evidence for this variant shows: No reports in databases. Therefore, this criterion is not applied at any strength.
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: It is a missense variant, not synonymous. Therefore, this criterion is not applied at any strength.