rs41564016

Variant names:

• chr15-89323415-G-A
• rs41564016
• NM_002693.3:c.2254C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89323415-G-A
• chr15-89323415-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002693.3(POLG):​c.2254C>T​(p.Leu752Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,610,096 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L752L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 33)
  • Exomes 𝑓: 0.011 (155 hom.)
• Consequence: POLG NM_002693.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 2.79
• 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]

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-89323415-G-A is Benign according to our data. Variant chr15-89323415-G-A is described in ClinVar as Benign. ClinVar VariationId is 129991.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1779/152330) while in subpopulation NFE AF = 0.0137 (933/68036). AF 95% confidence interval is 0.013. There are 28 homozygotes in GnomAd4. There are 956 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,AD gene

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.2254C>T	p.Leu752Leu	synonymous	Exon 13 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.2254C>T	p.Leu752Leu	synonymous	Exon 13 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.2254C>T	p.Leu752Leu	synonymous	Exon 13 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.2254C>T	p.Leu752Leu	synonymous	Exon 13 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.2254C>T	p.Leu752Leu	synonymous	Exon 13 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1782 AN: 152212 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.0128 AC: 3212 AN: 251192 AF XY: 0.0130

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0112 AC: 16334 AN: 1457766 Hom.: 155 Cov.: 30 AF XY: 0.0113 AC XY: 8181 AN XY: 725474

African (AFR) AF: 0.000779 AC: 26 AN: 33396

American (AMR) AF: 0.00277 AC: 124 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00670 AC: 175 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00675 AC: 582 AN: 86192

European-Finnish (FIN) AF: 0.0542 AC: 2892 AN: 53406

Middle Eastern (MID) AF: 0.00643 AC: 37 AN: 5756

European-Non Finnish (NFE) AF: 0.0108 AC: 11964 AN: 1108274

Other (OTH) AF: 0.00886 AC: 534 AN: 60246

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152330 Hom.: 28 Cov.: 33 AF XY: 0.0128 AC XY: 956 AN XY: 74484

African (AFR) AF: 0.00173 AC: 72 AN: 41576

American (AMR) AF: 0.00366 AC: 56 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00952 AC: 46 AN: 4834

European-Finnish (FIN) AF: 0.0583 AC: 619 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 933 AN: 68036

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.0103 Hom.: 15

Bravo AF: 0.00677

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0106

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mitochondrial disease (1)
-	-	1	POLG-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.5
DANN	Benign	0.70
PhyloP100		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs41564016; hg19: chr15-89866646;