NM_002693.3:c.2157+92T>C

Variant names:

• chr15-89323723-A-G
• rs2072266
• NM_002693.3:c.2157+92T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.2157+92T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,098,046 control chromosomes in the GnomAD database, including 80,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9022 hom., cov: 33)
  • Exomes 𝑓: 0.38 (71145 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.09
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-89323723-A-G is Benign according to our data. Variant chr15-89323723-A-G is described in ClinVar as [Benign]. Clinvar id is 1257536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.2157+92T>C		intron_variant	Intron 12 of 22	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2157+92T>C		intron_variant	Intron 12 of 22		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2157+92T>C		intron_variant	Intron 12 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49963 AN: 151884 Hom.: 9019 Cov.: 33

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.383 AC: 362238 AN: 946044 Hom.: 71145 Cov.: 13 AF XY: 0.385 AC XY: 189423 AN XY: 492418

African (AFR) AF: 0.170 AC: 4013 AN: 23612

American (AMR) AF: 0.368 AC: 16105 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 8512 AN: 22830

East Asian (EAS) AF: 0.308 AC: 11493 AN: 37358

South Asian (SAS) AF: 0.397 AC: 30113 AN: 75902

European-Finnish (FIN) AF: 0.456 AC: 24031 AN: 52708

Middle Eastern (MID) AF: 0.348 AC: 1154 AN: 3320

European-Non Finnish (NFE) AF: 0.390 AC: 250769 AN: 643314

Other (OTH) AF: 0.371 AC: 16048 AN: 43214

GnomAD4 genome AF: 0.329 AC: 49970 AN: 152002 Hom.: 9022 Cov.: 33 AF XY: 0.336 AC XY: 24978 AN XY: 74282

African (AFR) AF: 0.177 AC: 7335 AN: 41476

American (AMR) AF: 0.332 AC: 5068 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1233 AN: 3462

East Asian (EAS) AF: 0.321 AC: 1656 AN: 5162

South Asian (SAS) AF: 0.390 AC: 1880 AN: 4822

European-Finnish (FIN) AF: 0.469 AC: 4947 AN: 10546

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26729 AN: 67946

Other (OTH) AF: 0.320 AC: 676 AN: 2110

Alfa AF: 0.364 Hom.: 1329

Bravo AF: 0.314

Asia WGS AF: 0.330 AC: 1146 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 47. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.75
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs2072266; hg19: chr15-89866954; COSMIC: COSV51521070; COSMIC: COSV51521070;