12-132625719-C-G

Position:

• chr12-132625719-C-G

Variant summary

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

The NM_006231.4(POLE):​c.6583G>C​(p.Asp2195His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2195N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.39

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.6583G>C	p.Asp2195His	missense_variant	47/49	ENST00000320574.10
POLE	XM_011534795.4	c.6583G>C	p.Asp2195His	missense_variant	47/48
POLE	XM_011534797.4	c.5662G>C	p.Asp1888His	missense_variant	39/40
POLE	XM_011534802.4	c.3571G>C	p.Asp1191His	missense_variant	23/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6583G>C	p.Asp2195His	missense_variant	47/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.052	T;T
Polyphen		0.84	P;.
Vest4		0.66
MutPred		0.68		Gain of catalytic residue at Y2194 (P = 0.0013);.;
MVP		0.49
MPC		0.76
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.49

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: rs1472336573; hg19: chr12-133202305;