chr12-132664477-C-T

Variant names:

• chr12-132664477-C-T
• rs5744833
• NM_006231.4:c.2469-15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.2469-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,608,352 control chromosomes in the GnomAD database, including 2,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (1041 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (1020 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.358
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-132664477-C-T is Benign according to our data. Variant chr12-132664477-C-T is described in ClinVar as Benign. ClinVar VariationId is 380223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 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.2469-15G>A		intron	N/A	NP_006222.2	Q07864

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.2469-15G>A		intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.2388-15G>A		intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*1516-15G>A		intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9874 AN: 152138 Hom.: 1034 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0175 AC: 4391 AN: 250480 AF XY: 0.0127

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00697 AC: 10150 AN: 1456096 Hom.: 1020 Cov.: 30 AF XY: 0.00604 AC XY: 4376 AN XY: 724758

African (AFR) AF: 0.234 AC: 7811 AN: 33398

American (AMR) AF: 0.0128 AC: 571 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86136

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53004

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5752

European-Non Finnish (NFE) AF: 0.000621 AC: 687 AN: 1107126

Other (OTH) AF: 0.0156 AC: 941 AN: 60196

GnomAD4 genome AF: 0.0651 AC: 9914 AN: 152256 Hom.: 1041 Cov.: 32 AF XY: 0.0623 AC XY: 4637 AN XY: 74442

African (AFR) AF: 0.226 AC: 9370 AN: 41532

American (AMR) AF: 0.0233 AC: 356 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68016

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0280 Hom.: 136

Bravo AF: 0.0743

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Polymerase proofreading-related adenomatous polyposis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.27
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5744833; hg19: chr12-133241063;