NM_006231.4:c.5570A>C

Variant names:

• chr12-132638122-T-G
• NM_006231.4:c.5570A>C

Variant summary

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

The NM_006231.4(POLE):​c.5570A>C​(p.Lys1857Thr) variant causes a missense change. 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. K1857R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19

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 rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.5570A>C	p.Lys1857Thr	missense_variant	Exon 41 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5570A>C	p.Lys1857Thr	missense_variant	Exon 41 of 48		XP_011533097.1
POLE	XM_011534797.4	c.4649A>C	p.Lys1550Thr	missense_variant	Exon 33 of 40		XP_011533099.1
POLE	XM_011534802.4	c.2558A>C	p.Lys853Thr	missense_variant	Exon 17 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5570A>C	p.Lys1857Thr	missense_variant	Exon 41 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.20
Sift	Benign	0.060	T;T
Sift4G	Uncertain	0.059	T;T
Polyphen		0.29	B;.
Vest4		0.63
MutPred		0.42		Gain of catalytic residue at R1858 (P = 0.004);.;
MVP		0.45
MPC		0.65
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.36
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133214708;