rs104894632

Variant names:

• chr17-64477929-C-T
• rs104894632
• NM_007215.4:c.1352G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007215.4(POLG2):​c.1352G>A​(p.Gly451Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLG2 NM_007215.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.38

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: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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 17-64477929-C-T is Pathogenic according to our data. Variant chr17-64477929-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG2	NM_007215.4	c.1352G>A	p.Gly451Glu	missense_variant	Exon 8 of 8	ENST00000539111.7	NP_009146.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG2	ENST00000539111.7	c.1352G>A	p.Gly451Glu	missense_variant	Exon 8 of 8	1	NM_007215.4	ENSP00000442563.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

POLG2-related disorder Pathogenic:1

Aug 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLG2 c.1352G>A (p.Gly451Glu) results in a non-conservative amino acid change located in the Anticodon-binding domain (IPR004154) and C-terminal domain (IPR042064) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251208 control chromosomes (gnomAD). c.1352G>A has been reported in the literature in at least one heterozygous individual affected with late-onset autosomal-dominant progressive external ophthalmoplegia with a positive family history of disease (e.g., Longley_2006). These data suggest the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant displays a severe defect in its ability to physically associate with the catalytic subunit and is thus unable to enhance processivity of the holoenzyme (e.g., Longley_2006, Chan_2009, Young_2011). Experimental studies also found that the variant displayed a dominant negative effect, leading to loss of homodimeric polymerase gamma acitivty and substantial impairment of heterodimeric activity in complex with the wild-type (Young_2015). The following publications have been ascertained in the context of this evaluation (PMID: 19513667, 16685652, 21138766, 21555342, 26123486). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG2: PM1, PM2, PS3:Supporting, PS4:Supporting -

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

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.96		Gain of disorder (P = 0.0646);
MVP		0.99
MPC		0.68
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.79

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: rs104894632; hg19: chr17-62474046;