17-64480312-G-A

Position:

chr17-64480312-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007215.4(POLG2):c.1269C>T(p.Ser423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,572,444 control chromosomes in the GnomAD database, including 3,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 638 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3018 hom. )

Consequence

POLG2
NM_007215.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.440

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:):

MILR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 17-64480312-G-A is Benign according to our data. Variant chr17-64480312-G-A is described in ClinVar as [Benign]. Clinvar id is 138784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-64480312-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG2	NM_007215.4 linkuse as main transcript	c.1269C>T	p.Ser423=	synonymous_variant	7/8	ENST00000539111.7	NP_009146.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG2	ENST00000539111.7 linkuse as main transcript	c.1269C>T	p.Ser423=	synonymous_variant	7/8	1	NM_007215.4	ENSP00000442563	P1

Frequencies

GnomAD3 genomes

AF:

0.0823

AC:

12509

AN:

151986

Hom.:

637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.0328

Gnomad SAS

AF:

0.0439

Gnomad FIN

AF:

0.0583

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0628

Gnomad OTH

AF:

0.0714

GnomAD3 exomes

AF:

0.0729

AC:

18300

AN:

250934

Hom.:

850

AF XY:

0.0681

AC XY:

9235

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.0519

Gnomad EAS exome

AF:

0.0305

Gnomad SAS exome

AF:

0.0424

Gnomad FIN exome

AF:

0.0620

Gnomad NFE exome

AF:

0.0623

Gnomad OTH exome

AF:

0.0679

GnomAD4 exome

AF:

0.0596

AC:

84616

AN:

1420340

Hom.:

3018

Cov.:

AF XY:

0.0589

AC XY:

41734

AN XY:

708876

show subpopulations

Gnomad4 AFR exome

AF:

0.109

Gnomad4 AMR exome

AF:

0.154

Gnomad4 ASJ exome

AF:

0.0527

Gnomad4 EAS exome

AF:

0.0342

Gnomad4 SAS exome

AF:

0.0417

Gnomad4 FIN exome

AF:

0.0624

Gnomad4 NFE exome

AF:

0.0567

Gnomad4 OTH exome

AF:

0.0576

GnomAD4 genome

AF:

0.0823

AC:

12516

AN:

152104

Hom.:

638

Cov.:

AF XY:

0.0844

AC XY:

6276

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.0568

Gnomad4 EAS

AF:

0.0326

Gnomad4 SAS

AF:

0.0440

Gnomad4 FIN

AF:

0.0583

Gnomad4 NFE

AF:

0.0628

Gnomad4 OTH

AF:

0.0706

Alfa

AF:

0.0675

Hom.:

193

Bravo

AF:

0.0871

Asia WGS

AF:

0.0450

AC:

158

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 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. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.4

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over