4-56986390-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000938.3(POLR2B):​c.56C>G​(p.Pro19Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,518 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2B	NM_000938.3	c.56C>G	p.Pro19Arg	missense_variant	Exon 2 of 25	ENST00000314595.6	NP_000929.1
POLR2B	NM_001303269.2	c.35C>G	p.Pro12Arg	missense_variant	Exon 3 of 26		NP_001290198.1
POLR2B	NM_001303268.2	c.-19C>G		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>G	p.Pro19Arg	missense_variant	Exon 2 of 25	1	NM_000938.3	ENSP00000312735.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460518 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726662

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T;.;T;T
Eigen	Benign	0.046
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.55	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	.;L;.;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D;D;D;D;D
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.16	.;B;.;.;B
Vest4		0.75, 0.67, 0.75
MutPred		0.42		Loss of catalytic residue at P19 (P = 0.0102);Loss of catalytic residue at P19 (P = 0.0102);.;.;Loss of catalytic residue at P19 (P = 0.0102);
MVP		0.88
MPC		1.3
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57852556;