4-56986390-C-T

Variant names:

• chr4-56986390-C-T
• rs762792945
• NM_000938.3:c.56C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001303268.2(POLR2B):​c.-19C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: POLR2B NM_001303268.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2B	NM_000938.3	c.56C>T	p.Pro19Leu	missense_variant	Exon 2 of 25	ENST00000314595.6	NP_000929.1
POLR2B	NM_001303268.2	c.-19C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 24		NP_001290197.1
POLR2B	NM_001303269.2	c.35C>T	p.Pro12Leu	missense_variant	Exon 3 of 26		NP_001290198.1
POLR2B	NM_001303268.2	c.-19C>T		5_prime_UTR_variant	Exon 2 of 24		NP_001290197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2B	ENST00000314595.6	c.56C>T	p.Pro19Leu	missense_variant	Exon 2 of 25	1	NM_000938.3	ENSP00000312735.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251314 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460516 Hom.: 0 Cov.: 28 AF XY: 0.00000688 AC XY: 5 AN XY: 726660

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>T (p.P19L) alteration is located in exon 2 (coding exon 2) of the POLR2B gene. This alteration results from a C to T substitution at nucleotide position 56, causing the proline (P) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T;T;.;T;T
Eigen	Benign	0.044
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.7	.;L;.;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D;N;N;D;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.15	.;B;.;.;B
Vest4		0.75, 0.64, 0.74
MutPred		0.45		Loss of catalytic residue at P19 (P = 0.0409);Loss of catalytic residue at P19 (P = 0.0409);.;.;Loss of catalytic residue at P19 (P = 0.0409);
MVP		0.79
MPC		1.2
ClinPred		0.89	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs762792945; hg19: chr4-57852556;