chr4-57017210-C-T

Variant names:

• chr4-57017210-C-T
• rs1723396043
• NM_000938.3:c.2123C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000938.3(POLR2B):​c.2123C>T​(p.Ala708Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90
• Publications: 0 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_pathogenic. The variant received 8 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, 0.971
• PP5: Variant 4-57017210-C-T is Pathogenic according to our data. Variant chr4-57017210-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 916568.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2123C>T	p.Ala708Val	missense	Exon 15 of 25	NP_000929.1	P30876
	POLR2B	NM_001303269.2		c.2102C>T	p.Ala701Val	missense	Exon 16 of 26	NP_001290198.1	C9J2Y9
	POLR2B	NM_001303268.2		c.1898C>T	p.Ala633Val	missense	Exon 14 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.2123C>T	p.Ala708Val	missense	Exon 15 of 25	ENSP00000312735.5	P30876
	POLR2B	ENST00000381227.5	TSL:5	c.2123C>T	p.Ala708Val	missense	Exon 16 of 26	ENSP00000370625.1	P30876
	POLR2B	ENST00000441246.6	TSL:2	c.2102C>T	p.Ala701Val	missense	Exon 16 of 26	ENSP00000391452.2	C9J2Y9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Esophageal atresia/tracheoesophageal fistula (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.91		Loss of sheet (P = 0.0457)
MVP		0.94
MPC		2.6
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.99
Mutation Taster		=33/67	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1723396043; hg19: chr4-57883376;