12-132665430-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006231.4(POLE):c.2340G>A(p.Ser780Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,611,578 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S780S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 51 hom., cov: 31)

Exomes 𝑓: 0.023 ( 480 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -3.78

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-132665430-C-T is Benign according to our data. Variant chr12-132665430-C-T is described in ClinVar as Benign. ClinVar VariationId is 380225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.78 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0207 (3151/152256) while in subpopulation EAS AF = 0.028 (145/5180). AF 95% confidence interval is 0.0265. There are 51 homozygotes in GnomAd4. There are 1600 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 51 AD,AR gene

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.2340G>A	p.Ser780Ser	synonymous	Exon 21 of 49	NP_006222.2	Q07864

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLE	ENST00000320574.10	TSL:1 MANE Select	c.2340G>A	p.Ser780Ser	synonymous	Exon 21 of 49	ENSP00000322570.5	Q07864
POLE	ENST00000535270.5	TSL:1	c.2259G>A	p.Ser753Ser	synonymous	Exon 20 of 48	ENSP00000445753.1	F5H1D6
POLE	ENST00000537064.5	TSL:1	n.*1387G>A		non_coding_transcript_exon	Exon 21 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes

AF:

0.0207

AC:

3153

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.0279

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0235

AC:

5866

AN:

249490

AF XY:

0.0241

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.0339

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.0234

AC:

34091

AN:

1459322

Hom.:

480

Cov.:

AF XY:

0.0237

AC XY:

17200

AN XY:

726062

show subpopulations

African (AFR)

AF:

0.00359

AC:

120

AN:

33470

American (AMR)

AF:

0.0125

AC:

557

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

444

AN:

26134

East Asian (EAS)

AF:

0.0290

AC:

1152

AN:

39698

South Asian (SAS)

AF:

0.0217

AC:

1871

AN:

86258

European-Finnish (FIN)

AF:

0.0419

AC:

2146

AN:

51206

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0238

AC:

26455

AN:

1111714

Other (OTH)

AF:

0.0213

AC:

1283

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1744

3488

5231

6975

8719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

918

1836

2754

3672

4590

<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:

0.0207

AC:

3151

AN:

152256

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1600

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00426

AC:

177

AN:

41574

American (AMR)

AF:

0.0187

AC:

286

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.0280

AC:

145

AN:

5180

South Asian (SAS)

AF:

0.0259

AC:

125

AN:

4822

European-Finnish (FIN)

AF:

0.0411

AC:

436

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0275

AC:

1871

AN:

68006

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

150

301

451

602

752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0217

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.0380

AC:

132

AN:

3478

EpiCase

AF:

0.0231

EpiControl

AF:

0.0224

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

Carcinoma of colon (1)

Colorectal cancer, susceptibility to, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.031

(source)

DANN

Benign

0.56

PhyloP100

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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