1-92307219-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024813.3(RPAP2):c.431C>T(p.Ser144Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,611,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )
Consequence
RPAP2
NM_024813.3 missense
NM_024813.3 missense
Scores
9
5
1
Clinical Significance
Conservation
PhyloP100: 6.55
Genes affected
RPAP2 (HGNC:25791): (RNA polymerase II associated protein 2) Enables RNA polymerase II CTD heptapeptide repeat phosphatase activity. Involved in dephosphorylation of RNA polymerase II C-terminal domain and snRNA transcription. Located in cytosol and nucleolus. Part of RNA polymerase II, holoenzyme. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.966
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPAP2 | NM_024813.3 | c.431C>T | p.Ser144Phe | missense_variant | 6/13 | ENST00000610020.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPAP2 | ENST00000610020.2 | c.431C>T | p.Ser144Phe | missense_variant | 6/13 | 1 | NM_024813.3 | P1 | |
RPAP2 | ENST00000484158.1 | n.305C>T | non_coding_transcript_exon_variant | 5/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249228Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134592
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GnomAD4 exome AF: 0.0000418 AC: 61AN: 1459830Hom.: 0 Cov.: 29 AF XY: 0.0000372 AC XY: 27AN XY: 726032
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2024 | The c.431C>T (p.S144F) alteration is located in exon 6 (coding exon 6) of the RPAP2 gene. This alteration results from a C to T substitution at nucleotide position 431, causing the serine (S) at amino acid position 144 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of methylation at K145 (P = 0.0987);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at