rs2238296

chr15-89332098-A-G

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.659+998T>C		intron_variant		ENST00000268124.11
POLGARF	NM_001406557.1	c.714+998T>C		intron_variant
POLG	NM_001126131.2	c.659+998T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.659+998T>C		intron_variant		1	NM_002693.3	P1
POLGARF	ENST00000706918.1	c.714+998T>C		intron_variant				P1

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

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 1.00

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

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.432

Alfa AF: 0.435 Hom.: 3317

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
Dann	Benign	0.73

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

LitVar

Other links and lift over

dbSNP: rs2238296; hg19: chr15-89875329;