12-132632300-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006231.4(POLE):c.6330+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,601,652 control chromosomes in the GnomAD database, including 170,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19553 hom., cov: 32)

Exomes 𝑓: 0.45 ( 151158 hom. )

Consequence

POLE
NM_006231.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.184

Publications

10 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

POLE-related polyposis and colorectal cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal cancer, susceptibility to, 12
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
facial dysmorphism-immunodeficiency-livedo-short stature syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
Inheritance: AR Classification: STRONG Submitted by: G2P
IMAGe syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Polymerase proofreading-related adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POLE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 12-132632300-C-T is Benign according to our data. Variant chr12-132632300-C-T is described in ClinVar as Benign. ClinVar VariationId is 380218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.6330+15G>A		intron	N/A	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.6330+15G>A	intron	N/A	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.6249+15G>A	intron	N/A	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*6081+15G>A	intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75845

AN:

151806

Hom.:

19538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.591

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.381

Gnomad EAS

AF:

0.701

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.500

GnomAD2 exomes

AF:

0.494

AC:

122871

AN:

248930

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.584

Gnomad AMR exome

AF:

0.571

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.704

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.430

Gnomad OTH exome

AF:

0.472

GnomAD4 exome

AF:

0.452

AC:

654914

AN:

1449730

Hom.:

151158

Cov.:

AF XY:

0.454

AC XY:

327967

AN XY:

721740

show subpopulations

African (AFR)

AF:

0.582

AC:

19356

AN:

33246

American (AMR)

AF:

0.565

AC:

25183

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

10098

AN:

26042

East Asian (EAS)

AF:

0.697

AC:

27627

AN:

39634

South Asian (SAS)

AF:

0.546

AC:

46916

AN:

85990

European-Finnish (FIN)

AF:

0.427

AC:

22785

AN:

53368

Middle Eastern (MID)

AF:

0.501

AC:

2827

AN:

5648

European-Non Finnish (NFE)

AF:

0.429

AC:

472550

AN:

1101332

Other (OTH)

AF:

0.460

AC:

27572

AN:

59904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

16094

32189

48283

64378

80472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14556

29112

43668

58224

72780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.500

AC:

75892

AN:

151922

Hom.:

19553

Cov.:

AF XY:

0.502

AC XY:

37291

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.590

AC:

24446

AN:

41408

American (AMR)

AF:

0.543

AC:

8295

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

1323

AN:

3468

East Asian (EAS)

AF:

0.701

AC:

3614

AN:

5156

South Asian (SAS)

AF:

0.558

AC:

2686

AN:

4814

European-Finnish (FIN)

AF:

0.433

AC:

4567

AN:

10538

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.434

AC:

29466

AN:

67958

Other (OTH)

AF:

0.502

AC:

1056

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1928

3857

5785

7714

9642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.456

Hom.:

3077

Bravo

AF:

0.510

Asia WGS

AF:

0.578

AC:

2008

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Colorectal cancer, susceptibility to, 12 (1)

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (1)

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (1)

POLE-related polyposis and colorectal cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.59

(source)

DANN

Benign

0.47

PhyloP100

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over