rs148101254

Positions:

• chr17-64492910-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_007215.4(POLG2):​c.674G>A​(p.Arg225Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,614,048 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: POLG2 NM_007215.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.0500

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 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017912477).
• BP6: Variant 17-64492910-C-T is Benign according to our data. Variant chr17-64492910-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 324559.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG2	NM_007215.4	c.674G>A	p.Arg225Gln	missense_variant	2/8	ENST00000539111.7	NP_009146.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG2	ENST00000539111.7	c.674G>A	p.Arg225Gln	missense_variant	2/8	1	NM_007215.4	ENSP00000442563.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251450 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135910

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000116

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43 AN XY: 727200

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74434

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000839 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the POLG2 protein (p.Arg225Gln). This variant is present in population databases (rs148101254, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POLG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 324559). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2016

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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.15
Sift	Benign	0.60	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.23
MVP		0.74
MPC		0.15
ClinPred		0.0052	T
GERP RS		1.1
Varity_R		0.045
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148101254; hg19: chr17-62489027; COSMIC: COSV73347032; COSMIC: COSV73347032;