12-132634290-G-C

Variant names:

• chr12-132634290-G-C
• rs201273415
• NM_006231.4:c.5900C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006231.4(POLE):​c.5900C>G​(p.Ala1967Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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: 6.8e-7 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06514549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.5900C>G	p.Ala1967Gly	missense_variant	Exon 43 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5900C>G	p.Ala1967Gly	missense_variant	Exon 43 of 48		XP_011533097.1
POLE	XM_011534797.4	c.4979C>G	p.Ala1660Gly	missense_variant	Exon 35 of 40		XP_011533099.1
POLE	XM_011534802.4	c.2888C>G	p.Ala963Gly	missense_variant	Exon 19 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5900C>G	p.Ala1967Gly	missense_variant	Exon 43 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248982 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134778

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: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.21
DANN	Benign	0.61
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.027
Sift	Benign	0.38	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.30		Gain of loop (P = 0.0166);.;
MVP		0.23
MPC		0.19
ClinPred		0.023	T
GERP RS		-3.9
Varity_R		0.025
gMVP		0.26

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: rs201273415; hg19: chr12-133210876;