15-89323820-C-G

Variant names:

• chr15-89323820-C-G
• rs755783536
• NM_002693.3:c.2152G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002693.3(POLG):​c.2152G>C​(p.Ala718Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A718V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 0 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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14884701).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.2152G>C	p.Ala718Pro	missense	Exon 12 of 23	NP_002684.1
	POLG	NM_001126131.2		c.2152G>C	p.Ala718Pro	missense	Exon 12 of 23	NP_001119603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.2152G>C	p.Ala718Pro	missense	Exon 12 of 23	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.2152G>C	p.Ala718Pro	missense	Exon 12 of 23	ENSP00000399851.2
	POLG	ENST00000636937.2	TSL:5	c.2152G>C	p.Ala718Pro	missense	Exon 12 of 23	ENSP00000516154.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461234 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111422

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.0	N
PhyloP100		-0.099
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.28
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.34	B
Vest4		0.35
MutPred		0.46		Gain of glycosylation at A718 (P = 0.0199)
MVP		0.89
MPC		0.20
ClinPred		0.082	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.47
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs755783536; hg19: chr15-89867051;