4-57015611-A-G

Position:

• chr4-57015611-A-G

Variant summary

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

The NM_000938.3(POLR2B):​c.1910A>G​(p.Lys637Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000044 in 1,364,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

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=0.32233495).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR2B	NM_000938.3	c.1910A>G	p.Lys637Arg	missense_variant	14/25	ENST00000314595.6	NP_000929.1
POLR2B	NM_001303269.2	c.1889A>G	p.Lys630Arg	missense_variant	15/26		NP_001290198.1
POLR2B	NM_001303268.2	c.1685A>G	p.Lys562Arg	missense_variant	13/24		NP_001290197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR2B	ENST00000314595.6	c.1910A>G	p.Lys637Arg	missense_variant	14/25	1	NM_000938.3	ENSP00000312735.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000440 AC: 6 AN: 1364946 Hom.: 0 Cov.: 26 AF XY: 0.00000148 AC XY: 1 AN XY: 677944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000570

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jun 02, 2023

The c.1910A>G (p.K637R) alteration is located in exon 14 (coding exon 14) of the POLR2B gene. This alteration results from a A to G substitution at nucleotide position 1910, causing the lysine (K) at amino acid position 637 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.;T;.
Eigen	Benign	0.036
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.2	L;.;.;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;.;N;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.16	T;.;T;T;.
Sift4G	Benign	0.26	T;.;T;T;.
Polyphen		0.0030	B;.;.;B;.
Vest4		0.14
MutPred		0.53		Loss of methylation at K637 (P = 0.0185);.;.;Loss of methylation at K637 (P = 0.0185);.;
MVP		0.80
MPC		1.1
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.39

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: rs1415302017; hg19: chr4-57881777;