rs61733782

chr17-64480312-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.440

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 -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	UniProt
POLG2	NM_007215.4	c.1269C>T	p.Ser423=	synonymous_variant	7/8	ENST00000539111.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12509 AN: 151986 Hom.: 637 Cov.: 32

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

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.: 23 AF XY: 0.0589 AC XY: 41734 AN XY: 708876

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.: 32 AF XY: 0.0844 AC XY: 6276 AN XY: 74344

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

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

Other links and lift over

dbSNP: rs61733782; hg19: chr17-62476429; COSMIC: COSV73376903; COSMIC: COSV73376903;