17-64496464-C-T

Variant names:

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

Variant summary

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

The NM_007215.4(POLG2):​c.505G>A​(p.Ala169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,601,182 control chromosomes in the GnomAD database, including 27,966 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (11392 hom., cov: 32)
  • Exomes 𝑓: 0.11 (16574 hom.)
• Consequence: POLG2 NM_007215.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.252
• Publications: 35 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0777327E-6).
• BP6: Variant 17-64496464-C-T is Benign according to our data. Variant chr17-64496464-C-T is described in ClinVar as Benign. ClinVar VariationId is 138782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

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.505G>A	p.Ala169Thr	missense	Exon 1 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.505G>A	p.Ala169Thr	missense	Exon 1 of 8	ENSP00000442563.2	Q9UHN1
	POLG2	ENST00000585141.5	TSL:1	n.556G>A		non_coding_transcript_exon	Exon 1 of 5
	POLG2	ENST00000913014.1		c.505G>A	p.Ala169Thr	missense	Exon 1 of 9	ENSP00000583073.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42248 AN: 151940 Hom.: 11356 Cov.: 32

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0969

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.151 AC: 37805 AN: 250614 AF XY: 0.137

Gnomad AFR exome AF: 0.724

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0314

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0941

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.111 AC: 160226 AN: 1449124 Hom.: 16574 Cov.: 31 AF XY: 0.109 AC XY: 78259 AN XY: 718206

African (AFR) AF: 0.729 AC: 24126 AN: 33100

American (AMR) AF: 0.209 AC: 9249 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2652 AN: 26000

East Asian (EAS) AF: 0.0354 AC: 1391 AN: 39324

South Asian (SAS) AF: 0.118 AC: 10164 AN: 86028

European-Finnish (FIN) AF: 0.116 AC: 6199 AN: 53334

Middle Eastern (MID) AF: 0.127 AC: 728 AN: 5726

European-Non Finnish (NFE) AF: 0.0889 AC: 97974 AN: 1101648

Other (OTH) AF: 0.130 AC: 7743 AN: 59724

GnomAD4 genome AF: 0.278 AC: 42332 AN: 152058 Hom.: 11392 Cov.: 32 AF XY: 0.276 AC XY: 20486 AN XY: 74332

African (AFR) AF: 0.704 AC: 29163 AN: 41444

American (AMR) AF: 0.245 AC: 3739 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3470

East Asian (EAS) AF: 0.0332 AC: 172 AN: 5176

South Asian (SAS) AF: 0.109 AC: 524 AN: 4812

European-Finnish (FIN) AF: 0.115 AC: 1217 AN: 10596

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0969 AC: 6585 AN: 67972

Other (OTH) AF: 0.219 AC: 463 AN: 2112

Alfa AF: 0.147 Hom.: 15686

Bravo AF: 0.305

TwinsUK AF: 0.0871 AC: 323

ALSPAC AF: 0.0841 AC: 324

ESP6500AA AF: 0.686 AC: 3023

ESP6500EA AF: 0.0962 AC: 827

ExAC AF: 0.157 AC: 19094

Asia WGS AF: 0.111 AC: 388 AN: 3478

EpiCase AF: 0.0952

EpiControl AF: 0.0980

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (2)
-	-	1	Mitochondrial DNA depletion syndrome 16 (hepatic type) (1)
-	-	1	Mitochondrial dna depletion syndrome 16B (neuroophthalmic type) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.25
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.93	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.58	T
Polyphen		0.0060	B
Vest4		0.023
MPC		0.13
ClinPred		0.0028	T
GERP RS		1.6
Varity_R		0.026
gMVP		0.099
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV56749110; COSMIC: COSV56749110;