GeneBe

15-89333627-TGCCGCCGCC-TGCCGCCGCCGCCGCC

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002693.3(POLG):​c.122_127dupGGCGGC​(p.Arg41_Arg42dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q43Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

POLG
NM_002693.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Publications

1 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]
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.122_127dupGGCGGC p.Arg41_Arg42dup conservative_inframe_insertion Exon 2 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.122_127dupGGCGGC p.Arg41_Arg42dup conservative_inframe_insertion Exon 2 of 23 NP_001119603.1 P54098E5KNU5
POLGARFNM_001430120.1 linkc.177_182dupGGCGGC p.Ala60_Ala61dup disruptive_inframe_insertion Exon 1 of 2 NP_001417049.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.122_127dupGGCGGC p.Arg41_Arg42dup conservative_inframe_insertion Exon 2 of 23 1 NM_002693.3 ENSP00000268124.5 P54098
POLGARFENST00000706918.1 linkc.177_182dupGGCGGC p.Ala60_Ala61dup disruptive_inframe_insertion Exon 1 of 2 ENSP00000516626.1 A0A3B3IS91

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.99e-7
AC:
1
AN:
1429754
Hom.:
0
Cov.:
32
AF XY:
0.00000141
AC XY:
1
AN XY:
709888
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32846
American (AMR)
AF:
0.00
AC:
0
AN:
41446
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25708
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38304
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83972
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
44444
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5678
European-Non Finnish (NFE)
AF:
9.11e-7
AC:
1
AN:
1098080
Other (OTH)
AF:
0.00
AC:
0
AN:
59276
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy Uncertain:1
Jun 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant, c.122_127dup, results in the insertion of 2 amino acid(s) of the POLG protein (p.Arg41_Arg42dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 852621). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs761080016; hg19: chr15-89876858; API