rs2307450

Variant names:

• chr15-89324193-C-T
• rs2307450
• NM_002693.3:c.1984G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-89324193-C-T
• chr15-89324193-C-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1 BS2

This summary comes from the ClinGen Evidence Repository: The c.1984G>A (p.Glu662Lys) variant in POLG has been reported with an allele frequency in the population databases: 0.9 % in gnomAD and in the Latino population at 7% (BA1). It is also seen in the homozygous state in 112 individuals in gnomAD and 42 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA285511/MONDO:0044970/014

• Frequency:
  • Genomes: 𝑓 0.0056 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (143 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 0.538
• Publications: 11 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, 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

Specifications for POLG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1984G>A	p.Glu662Lys	missense	Exon 11 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.1984G>A	p.Glu662Lys	missense	Exon 11 of 23	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.1984G>A	p.Glu662Lys	missense	Exon 11 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.1984G>A	p.Glu662Lys	missense	Exon 11 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.1984G>A	p.Glu662Lys	missense	Exon 11 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152234 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0101 AC: 2535 AN: 249974 AF XY: 0.00769

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.0708

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000944

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00703

GnomAD4 exome AF: 0.00244 AC: 3562 AN: 1461202 Hom.: 143 Cov.: 32 AF XY: 0.00210 AC XY: 1525 AN XY: 726906

African (AFR) AF: 0.000777 AC: 26 AN: 33478

American (AMR) AF: 0.0695 AC: 3109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.0000758 AC: 4 AN: 52778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000232 AC: 258 AN: 1111982

Other (OTH) AF: 0.00262 AC: 158 AN: 60384

GnomAD4 genome AF: 0.00559 AC: 851 AN: 152352 Hom.: 23 Cov.: 33 AF XY: 0.00621 AC XY: 463 AN XY: 74504

African (AFR) AF: 0.000722 AC: 30 AN: 41576

American (AMR) AF: 0.0502 AC: 768 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00865

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mitochondrial disease (1)
-	-	1	POLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.54
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.21
Sift	Benign	0.25	T
Sift4G	Benign	0.75	T
Polyphen		0.0020	B
Vest4		0.32
MPC		0.17
ClinPred		0.0073	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.49
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2307450; hg19: chr15-89867424;