17-64496464-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007215.4(POLG2):c.505G>A(p.Ala169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,601,182 control chromosomes in the GnomAD database, including 27,966 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 11392 hom., cov: 32)

Exomes 𝑓: 0.11 ( 16574 hom. )

Consequence

POLG2
NM_007215.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.252

Publications

35 publications found

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 was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=2.0777327E-6).

BP6

Variant 17-64496464-C-T is Benign according to our data. Variant chr17-64496464-C-T is described in ClinVar as Benign. ClinVar VariationId is 138782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG2	NM_007215.4 link	c.505G>A	p.Ala169Thr	missense_variant	Exon 1 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.505G>A	p.Ala169Thr	missense_variant	Exon 1 of 8	1	NM_007215.4	ENSP00000442563.2		Q9UHN1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42248

AN:

151940

Hom.:

11356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.0333

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0969

Gnomad OTH

AF:

0.221

GnomAD2 exomes

AF:

0.151

AC:

37805

AN:

250614

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.205

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0314

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.0941

Gnomad OTH exome

AF:

0.122

GnomAD4 exome

AF:

0.111

AC:

160226

AN:

1449124

Hom.:

16574

Cov.:

AF XY:

0.109

AC XY:

78259

AN XY:

718206

show subpopulations

African (AFR)

AF:

0.729

AC:

24126

AN:

33100

American (AMR)

AF:

0.209

AC:

9249

AN:

44240

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

2652

AN:

26000

East Asian (EAS)

AF:

0.0354

AC:

1391

AN:

39324

South Asian (SAS)

AF:

0.118

AC:

10164

AN:

86028

European-Finnish (FIN)

AF:

0.116

AC:

6199

AN:

53334

Middle Eastern (MID)

AF:

0.127

AC:

728

AN:

5726

European-Non Finnish (NFE)

AF:

0.0889

AC:

97974

AN:

1101648

Other (OTH)

AF:

0.130

AC:

7743

AN:

59724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

6033

12066

18100

24133

30166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3872

7744

11616

15488

19360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.278

AC:

42332

AN:

152058

Hom.:

11392

Cov.:

AF XY:

0.276

AC XY:

20486

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.704

AC:

29163

AN:

41444

American (AMR)

AF:

0.245

AC:

3739

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

353

AN:

3470

East Asian (EAS)

AF:

0.0332

AC:

172

AN:

5176

South Asian (SAS)

AF:

0.109

AC:

524

AN:

4812

European-Finnish (FIN)

AF:

0.115

AC:

1217

AN:

10596

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0969

AC:

6585

AN:

67972

Other (OTH)

AF:

0.219

AC:

463

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1011

2022

3032

4043

5054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

336

672

1008

1344

1680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.147

Hom.:

15686

Bravo

AF:

0.305

TwinsUK

AF:

0.0871

AC:

323

ALSPAC

AF:

0.0841

AC:

324

ESP6500AA

AF:

0.686

AC:

3023

ESP6500EA

AF:

0.0962

AC:

827

ExAC

AF:

0.157

AC:

19094

Asia WGS

AF:

0.111

AC:

388

AN:

3478

EpiCase

AF:

0.0952

EpiControl

AF:

0.0980

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 30, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

Benign:2

Jan 13, 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. -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial dna depletion syndrome 16B (neuroophthalmic type)

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 16 (hepatic type)

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0072

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.8

PhyloP100

-0.25

PrimateAI

Benign

0.36

PROVEAN

Benign

0.93

REVEL

Benign

0.16

Sift

Benign

0.44

Sift4G

Benign

0.58

Polyphen

0.0060

Vest4

0.023

MPC

0.13

ClinPred

0.0028

GERP RS

1.6

Varity_R

0.026

gMVP

0.099

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over