NM_007215.4:c.505G>C

Variant names:

• chr17-64496464-C-G
• rs1427463
• NM_007215.4:c.505G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007215.4(POLG2):​c.505G>C​(p.Ala169Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A169T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLG2 NM_007215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.252
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30652553).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG2	NM_007215.4	MANE Select	c.505G>C	p.Ala169Pro	missense	Exon 1 of 8	NP_009146.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG2	ENST00000539111.7	TSL:1 MANE Select	c.505G>C	p.Ala169Pro	missense	Exon 1 of 8	ENSP00000442563.2
	POLG2	ENST00000585141.5	TSL:1	n.556G>C		non_coding_transcript_exon	Exon 1 of 5
	POLG2	ENST00000585104.2	TSL:3	n.476G>C		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449800 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718534

African (AFR) AF: 0.00 AC: 0 AN: 33130

American (AMR) AF: 0.00 AC: 0 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102216

Other (OTH) AF: 0.00 AC: 0 AN: 59750

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.25
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.42
Sift	Benign	0.30	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.17
MVP		0.73
MPC		0.17
ClinPred		0.40	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.47

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: rs1427463; hg19: chr17-62492582;