rs17850455

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007215.4(POLG2):c.1247G>C(p.Gly416Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0122 in 1,601,138 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 152 hom. )

Consequence

POLG2
NM_007215.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.68

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:27570): (mast cell immunoglobulin like receptor 1) Predicted to enable transmembrane signaling receptor activity. Predicted to be involved in several processes, including cell-cell adhesion via plasma-membrane adhesion molecules; mast cell degranulation; and negative regulation of mast cell activation. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MILR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013032943).

BP6

Variant 17-64480334-C-G is Benign according to our data. Variant chr17-64480334-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 138783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-64480334-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1526/152282) while in subpopulation NFE AF= 0.0151 (1028/68030). AF 95% confidence interval is 0.0143. There are 9 homozygotes in gnomad4. There are 687 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG2	NM_007215.4 link	c.1247G>C	p.Gly416Ala	missense_variant	Exon 7 of 8	ENST00000539111.7	NP_009146.2	Q9UHN1E5KS15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG2	ENST00000539111.7 link	c.1247G>C	p.Gly416Ala	missense_variant	Exon 7 of 8	1	NM_007215.4	ENSP00000442563.2		Q9UHN1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1526

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0102

AC:

2567

AN:

251182

Hom.:

AF XY:

0.0100

AC XY:

1358

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.0307

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000883

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0125

AC:

18053

AN:

1448856

Hom.:

152

Cov.:

AF XY:

0.0122

AC XY:

8770

AN XY:

721488

show subpopulations

Gnomad4 AFR exome

AF:

0.00154

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.0317

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00117

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0100

AC:

1526

AN:

152282

Hom.:

Cov.:

AF XY:

0.00923

AC XY:

687

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.00784

Gnomad4 ASJ

AF:

0.0300

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0133

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.00884

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0165

AC:

142

ExAC

AF:

0.0103

AC:

1251

EpiCase

AF:

0.0134

EpiControl

AF:

0.0125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG2: BS1, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Nov 08, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ExAC (NFE): 1087/66520=1.6% -

Hereditary spastic paraplegia

Benign:1

Nov 29, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.54

Sift

Benign

0.27

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MPC

0.61

ClinPred

0.019

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.65

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