rs1393017567

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-57030386-G-A
• chr4-57030386-G-C
• chr4-57030386-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000938.3(POLR2B):​c.3422G>A​(p.Arg1141His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,846 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: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -3 ACMG points.

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

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>A	p.Arg1141His	missense	Exon 24 of 25	NP_000929.1	P30876
	POLR2B	NM_001303269.2		c.3401G>A	p.Arg1134His	missense	Exon 25 of 26	NP_001290198.1	C9J2Y9
	POLR2B	NM_001303268.2		c.3197G>A	p.Arg1066His	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>A	p.Arg1141His	missense	Exon 24 of 25	ENSP00000312735.5	P30876
	POLR2B	ENST00000381227.5	TSL:5	c.3422G>A	p.Arg1141His	missense	Exon 25 of 26	ENSP00000370625.1	P30876
	POLR2B	ENST00000441246.6	TSL:2	c.3401G>A	p.Arg1134His	missense	Exon 25 of 26	ENSP00000391452.2	C9J2Y9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457734 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724960

African (AFR) AF: 0.0000300 AC: 1 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: 0.0000505 AC: 2 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: 1109260

Other (OTH) AF: 0.0000332 AC: 2 AN: 60220

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.6	L
PhyloP100		9.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.013	D
Sift4G	Benign	0.090	T
Polyphen		0.94	P
Vest4		0.52
MutPred		0.55		Loss of MoRF binding (P = 0.0148)
MVP		0.76
MPC		2.6
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.89
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs1393017567; hg19: chr4-57896552; COSMIC: COSV55272105; COSMIC: COSV55272105;