chr12-132632667-G-A

Variant names:

• chr12-132632667-G-A
• rs910631094
• NM_006231.4:c.6133C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006231.4(POLE):​c.6133C>T​(p.Pro2045Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30371034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.6133C>T	p.Pro2045Ser	missense_variant	Exon 44 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6133C>T	p.Pro2045Ser	missense_variant	Exon 44 of 48		XP_011533097.1
POLE	XM_011534797.4	c.5212C>T	p.Pro1738Ser	missense_variant	Exon 36 of 40		XP_011533099.1
POLE	XM_011534802.4	c.3121C>T	p.Pro1041Ser	missense_variant	Exon 20 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6133C>T	p.Pro2045Ser	missense_variant	Exon 44 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces proline with serine at codon 2045 of the POLE protein (p.Pro2045Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.26
Sift	Benign	0.045	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.012	B;.
Vest4		0.44
MutPred		0.51		Gain of catalytic residue at M2047 (P = 0.0017);.;
MVP		0.64
MPC		0.20
ClinPred		0.78	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs910631094; hg19: chr12-133209253;