dbSNP rs2238296: POLG:c.659+998T>C (chr15-89332098-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002693.3(POLG):c.659+998T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 152,076 control chromosomes in the GnomAD database, including 17,149 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 17147 hom., cov: 32)

Exomes 𝑓: 0.67 ( 2 hom. )

Consequence

POLG
NM_002693.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.548

Publications

6 publications found

Variant links:

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 links:

POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

POLGARF links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.659+998T>C	intron_variant	Intron 2 of 22	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.659+998T>C	intron_variant	Intron 2 of 22		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001430120.1 link	c.714+998T>C	intron_variant	Intron 1 of 1		NP_001417049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.659+998T>C		intron_variant	Intron 2 of 22	1	NM_002693.3	ENSP00000268124.5		P54098
POLGARF	ENST00000706918.1 link	c.714+998T>C		intron_variant	Intron 1 of 1			ENSP00000516626.1		A0A3B3IS91

Frequencies

GnomAD3 genomes

AF:

0.459

AC:

69810

AN:

151952

Hom.:

17119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.644

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.394

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.337

Gnomad SAS

AF:

0.396

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.435

GnomAD4 exome

AF:

0.667

AC:

AN:

Hom.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AC:

AN:

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.460

AC:

69877

AN:

152070

Hom.:

17147

Cov.:

AF XY:

0.462

AC XY:

34346

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.644

AC:

26719

AN:

41478

American (AMR)

AF:

0.394

AC:

6016

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1315

AN:

3472

East Asian (EAS)

AF:

0.338

AC:

1752

AN:

5180

South Asian (SAS)

AF:

0.397

AC:

1918

AN:

4826

European-Finnish (FIN)

AF:

0.462

AC:

4871

AN:

10532

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.381

AC:

25913

AN:

67984

Other (OTH)

AF:

0.432

AC:

912

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1855

3710

5565

7420

9275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.439

Hom.:

3480

Bravo

AF:

0.466

Asia WGS

AF:

0.376

AC:

1308

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.5

(source)

DANN

Benign

0.73

PhyloP100

-0.55

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over