12-132638059-C-G

Position:

• chr12-132638059-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_006231.4(POLE):​c.5633G>C​(p.Arg1878Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97

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]

POLE (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5633G>C	p.Arg1878Pro	missense_variant	41/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5633G>C	p.Arg1878Pro	missense_variant	41/48		XP_011533097.1
POLE	XM_011534797.4	c.4712G>C	p.Arg1571Pro	missense_variant	33/40		XP_011533099.1
POLE	XM_011534802.4	c.2621G>C	p.Arg874Pro	missense_variant	17/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5633G>C	p.Arg1878Pro	missense_variant	41/49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251470 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	0.0042
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.28
Sift	Benign	0.24	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.15	B;.
Vest4		0.81
MutPred		0.66		Gain of catalytic residue at K1877 (P = 0.0044);.;
MVP		0.45
MPC		0.36
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.71

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: rs374022997; hg19: chr12-133214645;