4-57017210-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 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. 12/21 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

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 916568.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2B	NM_000938.3	c.2123C>T	p.Ala708Val	missense_variant	Exon 15 of 25	ENST00000314595.6	NP_000929.1
POLR2B	NM_001303269.2	c.2102C>T	p.Ala701Val	missense_variant	Exon 16 of 26		NP_001290198.1
POLR2B	NM_001303268.2	c.1898C>T	p.Ala633Val	missense_variant	Exon 14 of 24		NP_001290197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2B	ENST00000314595.6	c.2123C>T	p.Ala708Val	missense_variant	Exon 15 of 25	1	NM_000938.3	ENSP00000312735.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Esophageal atresia/tracheoesophageal fistula Pathogenic:1

Jul 01, 2019

Shen Lab, Columbia University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M;.;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	D;D;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;T;D;D;.
Sift4G	Uncertain	0.024	D;.;D;D;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.95
MutPred		0.91		Loss of sheet (P = 0.0457);.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1723396043; hg19: chr4-57883376;