rs146504115

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_007215.4(POLG2):c.122G>A(p.Gly41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,613,876 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

POLG2
NM_007215.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.452

Variant links:

Genes affected

POLG2 (HGNC:9180): (DNA polymerase gamma 2, accessory subunit) This gene encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding and promotes processive DNA synthesis. Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.[provided by RefSeq, Sep 2009]

POLG2 links:

MILR1 (HGNC:):

MILR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004502833).

BP6

Variant 17-64496847-C-T is Benign according to our data. Variant chr17-64496847-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215021.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00163 (248/152304) while in subpopulation AFR AF= 0.0058 (241/41560). AF 95% confidence interval is 0.0052. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG2	NM_007215.4 linkuse as main transcript	c.122G>A	p.Gly41Glu	missense_variant	1/8	ENST00000539111.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG2	ENST00000539111.7 linkuse as main transcript	c.122G>A	p.Gly41Glu	missense_variant	1/8	1	NM_007215.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

248

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00582

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000414

AC:

104

AN:

251248

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00572

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000157

AC:

230

AN:

1461572

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00609

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.00163

AC:

248

AN:

152304

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00580

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.00179

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

POLG2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.0083

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.38

M_CAP

Benign

0.051

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.46

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Benign

0.17

Polyphen

0.025

Vest4

0.26

MVP

0.93

MPC

0.39

ClinPred

0.030

GERP RS

1.6

Varity_R

0.079

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over