rs17850455

chr17-64480334-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.68

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]

MILR1 (HGNC:):

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG2	NM_007215.4	c.1247G>C	p.Gly416Ala	missense_variant	7/8	ENST00000539111.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG2	ENST00000539111.7	c.1247G>C	p.Gly416Ala	missense_variant	7/8	1	NM_007215.4	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1526 AN: 152164 Hom.: 9 Cov.: 32

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.: 24 AF XY: 0.0100 AC XY: 1358 AN XY: 135792

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.: 25 AF XY: 0.0122 AC XY: 8770 AN XY: 721488

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.: 9 Cov.: 32 AF XY: 0.00923 AC XY: 687 AN XY: 74454

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.: 9

Bravo AF: 0.00884

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00295 AC: 13

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2011	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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% -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2022	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	POLG2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 29, 2021

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.54
Sift	Benign	0.27	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MPC		0.61
ClinPred		0.019	T
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

Other links and lift over

dbSNP: rs17850455; hg19: chr17-62476451;