12-132667656-C-T

Variant names:

• chr12-132667656-C-T
• rs117409343
• NM_006231.4:c.2174-8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.2174-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,613,788 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (179 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.001593
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.375
• Publications: 1 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=-0.77).
• BP6: Variant 12-132667656-C-T is Benign according to our data. Variant chr12-132667656-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1687/152308) while in subpopulation NFE AF = 0.0172 (1170/68034). AF 95% confidence interval is 0.0164. There are 9 homozygotes in GnomAd4. There are 805 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD 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.2174-8G>A		splice_region 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.2174-8G>A		splice_region intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.2093-8G>A		splice_region intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*1221-8G>A		splice_region intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1686 AN: 152190 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0119 AC: 2982 AN: 251098 AF XY: 0.0115

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0143 AC: 20861 AN: 1461480 Hom.: 179 Cov.: 31 AF XY: 0.0138 AC XY: 10059 AN XY: 727060

African (AFR) AF: 0.00179 AC: 60 AN: 33478

American (AMR) AF: 0.00881 AC: 394 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00846 AC: 221 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00336 AC: 290 AN: 86252

European-Finnish (FIN) AF: 0.0197 AC: 1046 AN: 53214

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18158 AN: 1111838

Other (OTH) AF: 0.0112 AC: 677 AN: 60380

GnomAD4 genome AF: 0.0111 AC: 1687 AN: 152308 Hom.: 9 Cov.: 32 AF XY: 0.0108 AC XY: 805 AN XY: 74466

African (AFR) AF: 0.00315 AC: 131 AN: 41570

American (AMR) AF: 0.00562 AC: 86 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

European-Finnish (FIN) AF: 0.0220 AC: 233 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1170 AN: 68034

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.0145 Hom.: 10

Bravo AF: 0.00996

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Carcinoma of colon (1)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.7
DANN	Benign	0.55
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.080
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: rs117409343; hg19: chr12-133244242;