chr4-57010866-T-C

Variant names:

• chr4-57010866-T-C
• NM_000938.3:c.1667T>C

Variant summary

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

The NM_000938.3(POLR2B):​c.1667T>C​(p.Ile556Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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.1667T>C	p.Ile556Thr	missense_variant	Exon 12 of 25	ENST00000314595.6	NP_000929.1
POLR2B	NM_001303269.2	c.1646T>C	p.Ile549Thr	missense_variant	Exon 13 of 26		NP_001290198.1
POLR2B	NM_001303268.2	c.1442T>C	p.Ile481Thr	missense_variant	Exon 11 of 24		NP_001290197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2B	ENST00000314595.6	c.1667T>C	p.Ile556Thr	missense_variant	Exon 12 of 25	1	NM_000938.3	ENSP00000312735.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1667T>C (p.I556T) alteration is located in exon 12 (coding exon 12) of the POLR2B gene. This alteration results from a T to C substitution at nucleotide position 1667, causing the isoleucine (I) at amino acid position 556 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M;.;.;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.2	N;.;N;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.044	D;.;D;D;.
Sift4G	Benign	0.19	T;.;T;T;.
Polyphen		0.021	B;.;.;B;.
Vest4		0.66
MutPred		0.49		Gain of disorder (P = 0.0169);.;.;Gain of disorder (P = 0.0169);.;
MVP		0.83
MPC		1.6
ClinPred		0.82	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.93

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: chr4-57877032;