4-57023570-G-A
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000938.3(POLR2B):c.2756G>A(p.Cys919Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
POLR2B
NM_000938.3 missense
NM_000938.3 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 8.00
Genes affected
POLR2B (HGNC:9188): (RNA polymerase II subunit B) This gene encodes the second largest subunit of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase that catalyzes the transcription of DNA into precursors of mRNA, snRNA and microRNA. This subunit and the largest subunit form opposite sides of the center cleft of Pol II. Deletion of the flap loop region of this subunit results in a decrease in the rate of transcriptional elongation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLR2B | NM_000938.3 | c.2756G>A | p.Cys919Tyr | missense_variant | 19/25 | ENST00000314595.6 | NP_000929.1 | |
POLR2B | NM_001303269.2 | c.2735G>A | p.Cys912Tyr | missense_variant | 20/26 | NP_001290198.1 | ||
POLR2B | NM_001303268.2 | c.2531G>A | p.Cys844Tyr | missense_variant | 18/24 | NP_001290197.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLR2B | ENST00000314595.6 | c.2756G>A | p.Cys919Tyr | missense_variant | 19/25 | 1 | NM_000938.3 | ENSP00000312735.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250906Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135618
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461660Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727146
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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 | Dec 15, 2022 | The c.2756G>A (p.C919Y) alteration is located in exon 19 (coding exon 19) of the POLR2B gene. This alteration results from a G to A substitution at nucleotide position 2756, causing the cysteine (C) at amino acid position 919 to be replaced by a tyrosine (Y). 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;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;.;.;N;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;D;.
REVEL
Uncertain
Sift
Pathogenic
D;.;D;D;.
Sift4G
Uncertain
D;.;D;D;.
Polyphen
P;.;.;P;.
Vest4
MutPred
Loss of methylation at K920 (P = 0.0144);.;.;Loss of methylation at K920 (P = 0.0144);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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