12-132649127-C-T

Position:

• chr12-132649127-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.4006-55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 1,578,468 control chromosomes in the GnomAD database, including 5,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (331 hom., cov: 33)
  • Exomes 𝑓: 0.079 (4839 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.495

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-132649127-C-T is Benign according to our data. Variant chr12-132649127-C-T is described in ClinVar as [Benign]. Clinvar id is 1264080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.4006-55G>A		intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4006-55G>A		intron_variant		1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8561 AN: 152204 Hom.: 330 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0967

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0487

GnomAD4 exome AF: 0.0786 AC: 112099 AN: 1426146 Hom.: 4839 Cov.: 31 AF XY: 0.0772 AC XY: 54410 AN XY: 704878

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.0304

Gnomad4 ASJ exome AF: 0.0964

Gnomad4 EAS exome AF: 0.0795

Gnomad4 SAS exome AF: 0.0315

Gnomad4 FIN exome AF: 0.0669

Gnomad4 NFE exome AF: 0.0863

Gnomad4 OTH exome AF: 0.0783

GnomAD4 genome AF: 0.0562 AC: 8558 AN: 152322 Hom.: 331 Cov.: 33 AF XY: 0.0545 AC XY: 4060 AN XY: 74476

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.0357

Gnomad4 ASJ AF: 0.0967

Gnomad4 EAS AF: 0.0742

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.0659

Gnomad4 NFE AF: 0.0822

Gnomad4 OTH AF: 0.0496

Alfa AF: 0.0691 Hom.: 382

Bravo AF: 0.0541

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.36

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: rs5744903; hg19: chr12-133225713;