Genetic Variant POLR2C:p.Thr12Arg (chr16-57462759-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_032940.3(POLR2C):c.35C>G(p.Thr12Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T12M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POLR2C
NM_032940.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.26

Publications

0 publications found

Variant links:

Genes affected

POLR2C (HGNC:9189): (RNA polymerase II subunit C) This gene encodes the third largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a cysteine rich region and exists as a heterodimer with another polymerase subunit, POLR2J. These two subunits form a core subassembly unit of the polymerase. A pseudogene has been identified on chromosome 21. [provided by RefSeq, Jul 2008]

POLR2C links:

ENSG00000260345 (HGNC:):

ENSG00000260345 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.8647 (below the threshold of 3.09). Trascript score misZ: 1.722 (below the threshold of 3.09).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032940.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2C	NM_032940.3	MANE Select	c.35C>G	p.Thr12Arg	missense	Exon 1 of 9	NP_116558.1	Q6FGR6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR2C	ENST00000219252.10	TSL:1 MANE Select	c.35C>G	p.Thr12Arg	missense	Exon 1 of 9	ENSP00000219252.4	P19387
POLR2C	ENST00000880578.1		c.35C>G	p.Thr12Arg	missense	Exon 1 of 8	ENSP00000550637.1
POLR2C	ENST00000562599.5	TSL:5	n.35C>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000456367.1	H3BRR2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456048

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.0000118

AC:

AN:

85102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109390

Other (OTH)

AF:

0.00

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.4

PhyloP100

7.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.56

Sift

Benign

0.16

Sift4G

Benign

0.84

Polyphen

0.96

Vest4

0.74

MutPred

0.35

Gain of solvent accessibility (P = 0.1505)

MVP

0.91

MPC

1.3

ClinPred

0.97

GERP RS

4.6

PromoterAI

-0.078

Neutral

(source)

Varity_R

0.66

gMVP

0.81

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over