16-57462801-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2PP5BS2_Supporting

The NM_032940.3(POLR2C):c.77C>G(p.Thr26Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,607,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

POLR2C
NM_032940.3 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.32

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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).

PP5

Variant 16-57462801-C-G is Pathogenic according to our data. Variant chr16-57462801-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1256028.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.77C>G	p.Thr26Ser	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.77C>G	p.Thr26Ser	missense	Exon 1 of 9	ENSP00000219252.4	P19387
POLR2C	ENST00000880578.1		c.77C>G	p.Thr26Ser	missense	Exon 1 of 8	ENSP00000550637.1
POLR2C	ENST00000562599.5	TSL:5	n.77C>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000456367.1	H3BRR2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000875

AC:

AN:

239890

AF XY:

0.0000922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000241

AC:

AN:

1455210

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

723546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

44194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.000607

AC:

AN:

39552

South Asian (SAS)

AF:

0.0000587

AC:

AN:

85184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52634

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108410

Other (OTH)

AF:

0.0000499

AC:

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

AF:

0.0000394

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000967

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000578

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Genetic non-acquired premature ovarian failure (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.29

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.5

PhyloP100

7.3

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.64

Sift

Uncertain

0.0060

Sift4G

Benign

0.075

Polyphen

0.93

Vest4

0.83

MutPred

0.50

Gain of relative solvent accessibility (P = 0.1571)

MVP

0.98

MPC

1.6

ClinPred

0.43

GERP RS

4.5

PromoterAI

-0.056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.79

Mutation Taster

=63/37

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over