rs17850455

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. G416G) has been classified 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

Publications

19 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=0.013032943).

BP6

Variant 17-64480334-C-G is Benign according to our data. Variant chr17-64480334-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138783.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 = 0.01 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007215.4. 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
	POLG2	NM_007215.4	MANE Select	c.1247G>C	p.Gly416Ala	missense	Exon 7 of 8	NP_009146.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLG2	ENST00000539111.7	TSL:1 MANE Select	c.1247G>C	p.Gly416Ala	missense	Exon 7 of 8	ENSP00000442563.2
POLG2	ENST00000913014.1		c.1271G>C	p.Gly424Ala	missense	Exon 8 of 9	ENSP00000583073.1
POLG2	ENST00000913015.1		c.1190G>C	p.Gly397Ala	missense	Exon 7 of 8	ENSP00000583074.1

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

GnomAD2 exomes

AF:

0.0102

AC:

2567

AN:

251182

AF XY:

0.0100

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 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

African (AFR)

AF:

0.00154

AC:

AN:

33176

American (AMR)

AF:

0.00392

AC:

175

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

821

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00117

AC:

101

AN:

85958

European-Finnish (FIN)

AF:

0.0157

AC:

830

AN:

52904

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0139

AC:

15274

AN:

1101450

Other (OTH)

AF:

0.0132

AC:

790

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

688

1376

2063

2751

3439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.0100

AC:

1526

AN:

152282

Hom.:

Cov.:

AF XY:

0.00923

AC XY:

687

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41564

American (AMR)

AF:

0.00784

AC:

120

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

104

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0133

AC:

141

AN:

10582

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1028

AN:

68030

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0151

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Hereditary spastic paraplegia (1)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

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

PhyloP100

6.7

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

Mutation Taster

=7/93

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over