chr15-89323923-A-G

Variant names:

• chr15-89323923-A-G
• rs2072267
• NM_002693.3:c.2071-22T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.2071-22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,597,192 control chromosomes in the GnomAD database, including 189,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25399 hom., cov: 33)
  • Exomes 𝑓: 0.47 (164286 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.271
• Publications: 19 publications found

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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-89323923-A-G is Benign according to our data. Variant chr15-89323923-A-G is described in ClinVar as Benign. ClinVar VariationId is 619385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.2071-22T>C		intron_variant	Intron 11 of 22	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2071-22T>C		intron_variant	Intron 11 of 22		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2071-22T>C		intron_variant	Intron 11 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.559 AC: 85008 AN: 152036 Hom.: 25354 Cov.: 33

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.527

GnomAD2 exomes AF: 0.488 AC: 122160 AN: 250382 AF XY: 0.485

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.473 AC: 683735 AN: 1445036 Hom.: 164286 Cov.: 28 AF XY: 0.473 AC XY: 340407 AN XY: 719832

African (AFR) AF: 0.797 AC: 26429 AN: 33150

American (AMR) AF: 0.451 AC: 20121 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12522 AN: 26040

East Asian (EAS) AF: 0.372 AC: 14731 AN: 39604

South Asian (SAS) AF: 0.485 AC: 41676 AN: 85912

European-Finnish (FIN) AF: 0.519 AC: 27710 AN: 53388

Middle Eastern (MID) AF: 0.487 AC: 2794 AN: 5740

European-Non Finnish (NFE) AF: 0.464 AC: 508448 AN: 1096744

Other (OTH) AF: 0.490 AC: 29304 AN: 59822

GnomAD4 genome AF: 0.559 AC: 85097 AN: 152156 Hom.: 25399 Cov.: 33 AF XY: 0.560 AC XY: 41658 AN XY: 74388

African (AFR) AF: 0.786 AC: 32653 AN: 41528

American (AMR) AF: 0.469 AC: 7175 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1613 AN: 3470

East Asian (EAS) AF: 0.390 AC: 2014 AN: 5164

South Asian (SAS) AF: 0.480 AC: 2317 AN: 4826

European-Finnish (FIN) AF: 0.527 AC: 5585 AN: 10592

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32024 AN: 67976

Other (OTH) AF: 0.522 AC: 1101 AN: 2108

Alfa AF: 0.465 Hom.: 3196

Bravo AF: 0.569

Asia WGS AF: 0.459 AC: 1594 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive sclerosing poliodystrophy Benign:2

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.2071-22T>C (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89323923A>G] 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. BA1:Minor allele frequency is too high for the Mitochondrial DNA depletion syndrome 4A (Alpers type). 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. -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 58. Only high quality variants are reported. -

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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLG-related disorder Benign:1

Jun 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Mitochondrial DNA depletion syndrome 4b Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072267; hg19: chr15-89867154; COSMIC: COSV51521765; COSMIC: COSV51521765;