chr4-57006910-C-T

Position:

• chr4-57006910-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000938.3(POLR2B):​c.1312C>T​(p.Arg438Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38372132).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR2B	NM_000938.3	c.1312C>T	p.Arg438Trp	missense_variant	10/25	ENST00000314595.6	NP_000929.1
POLR2B	NM_001303269.2	c.1291C>T	p.Arg431Trp	missense_variant	11/26		NP_001290198.1
POLR2B	NM_001303268.2	c.1087C>T	p.Arg363Trp	missense_variant	9/24		NP_001290197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR2B	ENST00000314595.6	c.1312C>T	p.Arg438Trp	missense_variant	10/25	1	NM_000938.3	ENSP00000312735.5
POLR2B	ENST00000381227.5	c.1312C>T	p.Arg438Trp	missense_variant	11/26	5		ENSP00000370625.1
POLR2B	ENST00000441246.6	c.1291C>T	p.Arg431Trp	missense_variant	11/26	2		ENSP00000391452.2
POLR2B	ENST00000431623.6	c.991C>T	p.Arg331Trp	missense_variant	9/24	2		ENSP00000391096.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251398 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460230 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726544

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.1312C>T (p.R438W) alteration is located in exon 10 (coding exon 10) of the POLR2B gene. This alteration results from a C to T substitution at nucleotide position 1312, causing the arginine (R) at amino acid position 438 to be replaced by a tryptophan (W). 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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;D;.
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L;.;.;L;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D;.;D;D;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;.;D;D;.
Sift4G	Uncertain	0.0040	D;.;D;D;.
Polyphen		0.99	D;.;.;D;.
Vest4		0.59
MutPred		0.41		Gain of ubiquitination at K436 (P = 0.0455);.;.;Gain of ubiquitination at K436 (P = 0.0455);.;
MVP		0.48
MPC		2.1
ClinPred		0.88	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs771972957; hg19: chr4-57873076;