rs2307450

chr15-89324193-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):c.1984G>A(p.Glu662Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,554 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (143 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 0.538

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLGARF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017949045).
• BP6: Variant 15-89324193-C-T is Benign according to our data. Variant chr15-89324193-C-T is described in ClinVar as [Benign]. Clinvar id is 21310.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-89324193-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1984G>A	p.Glu662Lys	missense_variant	11/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1256G>A		3_prime_UTR_variant	11/23
POLG	NM_001126131.2	c.1984G>A	p.Glu662Lys	missense_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1984G>A	p.Glu662Lys	missense_variant	11/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152234 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0101 AC: 2535 AN: 249974 Hom.: 115 AF XY: 0.00769 AC XY: 1040 AN XY: 135188

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.0708

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000944

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00703

GnomAD4 exome AF: 0.00244 AC: 3562 AN: 1461202 Hom.: 143 Cov.: 32 AF XY: 0.00210 AC XY: 1525 AN XY: 726906

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.0695

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000758

Gnomad4 NFE exome AF: 0.000232

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00559 AC: 851 AN: 152352 Hom.: 23 Cov.: 33 AF XY: 0.00621 AC XY: 463 AN XY: 74504

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00865

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 25, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2013	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 sclerosing poliodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.1984G>A (NP_002684.1:p.Glu662Lys) [GRCH38: NC_000015.10:g.89324193C>T] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

POLG-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mitochondrial disease Benign:1

Benign, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

May 07, 2021

The c.1984G>A (p.Glu662Lys) variant in POLG has been reported with an allele frequency in the population databases: 0.9 % in gnomAD and in the Latino population at 7% (BA1). It is also seen in the homozygous state in 112 individuals in gnomAD and 42 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.21
Sift	Benign	0.25	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0020	B;B
Vest4		0.32
MPC		0.17
ClinPred		0.0073	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2307450; hg19: chr15-89867424;