rs2238296

Variant names:

• chr15-89332098-A-G
• rs2238296
• NM_002693.3:c.659+998T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.548
• Publications: 6 publications found

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]

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. 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
	POLG	NM_002693.3	MANE Select	c.659+998T>C		intron	N/A	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.714+998T>C		intron	N/A	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.659+998T>C		intron	N/A	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.659+998T>C		intron	N/A	ENSP00000268124.5	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.714+998T>C		intron	N/A	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000442287.6	TSL:1	c.659+998T>C		intron	N/A	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69810 AN: 151952 Hom.: 17119 Cov.: 32

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: 4 AN: 6 Hom.: 2 AF XY: 0.500 AC XY: 2 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 4 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.460 AC: 69877 AN: 152070 Hom.: 17147 Cov.: 32 AF XY: 0.462 AC XY: 34346 AN XY: 74324

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.5
DANN	Benign	0.73
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2238296; hg19: chr15-89875329;