rs748106601

chr12-132632781-C-Achr12-132632781-C-Gchr12-132632781-C-T

Variant summary

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

The NM_006231.4(POLE):c.6019G>T(p.Val2007Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,830 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2007M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.6019G>T	p.Val2007Leu	missense_variant	44/49	ENST00000320574.10
POLE	XM_011534795.4	c.6019G>T	p.Val2007Leu	missense_variant	44/48
POLE	XM_011534797.4	c.5098G>T	p.Val1700Leu	missense_variant	36/40
POLE	XM_011534802.4	c.3007G>T	p.Val1003Leu	missense_variant	20/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6019G>T	p.Val2007Leu	missense_variant	44/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456830 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724936

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.053
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.18
Sift	Benign	0.61	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.77
MutPred		0.52		Gain of catalytic residue at Y2003 (P = 2e-04);.;
MVP		0.52
MPC		0.19
ClinPred		0.84	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs748106601; hg19: chr12-133209367;