12-132626308-G-C

Position:

• chr12-132626308-G-C

Variant summary

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

The NM_006231.4(POLE):​c.6340C>G​(p.Leu2114Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.78

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6340C>G	p.Leu2114Val	missense_variant	46/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6340C>G	p.Leu2114Val	missense_variant	46/48		XP_011533097.1
POLE	XM_011534797.4	c.5419C>G	p.Leu1807Val	missense_variant	38/40		XP_011533099.1
POLE	XM_011534802.4	c.3328C>G	p.Leu1110Val	missense_variant	22/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6340C>G	p.Leu2114Val	missense_variant	46/49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249424 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461252 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.18	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.93	P;.
Vest4		0.74
MutPred		0.49		Gain of catalytic residue at D2115 (P = 0);.;
MVP		0.58
MPC		0.58
ClinPred		0.93	D
GERP RS		0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1165241306; hg19: chr12-133202894;