POLG2 p.Asp386Glu

Variant names:

• chr17-64482952-A-T
• NM_007215.4:c.1158T>A
• POLG2 p.Asp386Glu

Your query was ambiguous. Multiple possible variants found:

• chr17-64482952-A-T
• chr17-64482952-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007215.4(POLG2):​c.1158T>A​(p.Asp386Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLG2 NM_007215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG2	NM_007215.4	MANE Select	c.1158T>A	p.Asp386Glu	missense	Exon 6 of 8	NP_009146.2	E5KS15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG2	ENST00000539111.7	TSL:1 MANE Select	c.1158T>A	p.Asp386Glu	missense	Exon 6 of 8	ENSP00000442563.2	Q9UHN1
	POLG2	ENST00000913014.1		c.1182T>A	p.Asp394Glu	missense	Exon 7 of 9	ENSP00000583073.1
	POLG2	ENST00000910209.1		c.1017T>A	p.Asp339Glu	missense	Exon 5 of 7	ENSP00000580268.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.93	N
REVEL	Pathogenic	0.65
Sift	Benign	0.32	T
Sift4G	Benign	0.14	T
Varity_R		0.16
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-62479069;