chr4-57030386-G-C

Variant names:

• chr4-57030386-G-C
• rs1393017567
• NM_000938.3:c.3422G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000938.3(POLR2B):​c.3422G>C​(p.Arg1141Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1141H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.75
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 6.6178 (above the threshold of 3.09). Trascript score misZ: 6.4623 (above the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000938.3. 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
	POLR2B	NM_000938.3	MANE Select	c.3422G>C	p.Arg1141Pro	missense	Exon 24 of 25	NP_000929.1	P30876
	POLR2B	NM_001303269.2		c.3401G>C	p.Arg1134Pro	missense	Exon 25 of 26	NP_001290198.1	C9J2Y9
	POLR2B	NM_001303268.2		c.3197G>C	p.Arg1066Pro	missense	Exon 23 of 24	NP_001290197.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2B	ENST00000314595.6	TSL:1 MANE Select	c.3422G>C	p.Arg1141Pro	missense	Exon 24 of 25	ENSP00000312735.5	P30876
	POLR2B	ENST00000381227.5	TSL:5	c.3422G>C	p.Arg1141Pro	missense	Exon 25 of 26	ENSP00000370625.1	P30876
	POLR2B	ENST00000441246.6	TSL:2	c.3401G>C	p.Arg1134Pro	missense	Exon 25 of 26	ENSP00000391452.2	C9J2Y9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248974 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.86e-7 AC: 1 AN: 1457738 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724960

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.0000227 AC: 1 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109264

Other (OTH) AF: 0.00 AC: 0 AN: 60220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.082	T
Polyphen		0.88	P
Vest4		0.75
MutPred		0.69		Loss of MoRF binding (P = 0.0028)
MVP		0.87
MPC		1.8
ClinPred		0.73	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.99
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1393017567; hg19: chr4-57896552;