15-89323923-A-G

Variant names:

• chr15-89323923-A-G
• rs2072267
• NM_002693.3:c.2071-22T>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.2071-22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,597,192 control chromosomes in the GnomAD database, including 189,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25399 hom., cov: 33)
  • Exomes 𝑓: 0.47 (164286 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.271
• Publications: 19 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=-0.91).
• BP6: Variant 15-89323923-A-G is Benign according to our data. Variant chr15-89323923-A-G is described in ClinVar as Benign. ClinVar VariationId is 619385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

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.2071-22T>C		intron	N/A	NP_002684.1
	POLG	NM_001126131.2		c.2071-22T>C		intron	N/A	NP_001119603.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.2071-22T>C		intron	N/A	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.2071-22T>C		intron	N/A	ENSP00000399851.2
	POLG	ENST00000636937.2	TSL:5	c.2071-22T>C		intron	N/A	ENSP00000516154.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 85008 AN: 152036 Hom.: 25354 Cov.: 33

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.527

GnomAD2 exomes AF: 0.488 AC: 122160 AN: 250382 AF XY: 0.485

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.473 AC: 683735 AN: 1445036 Hom.: 164286 Cov.: 28 AF XY: 0.473 AC XY: 340407 AN XY: 719832

African (AFR) AF: 0.797 AC: 26429 AN: 33150

American (AMR) AF: 0.451 AC: 20121 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12522 AN: 26040

East Asian (EAS) AF: 0.372 AC: 14731 AN: 39604

South Asian (SAS) AF: 0.485 AC: 41676 AN: 85912

European-Finnish (FIN) AF: 0.519 AC: 27710 AN: 53388

Middle Eastern (MID) AF: 0.487 AC: 2794 AN: 5740

European-Non Finnish (NFE) AF: 0.464 AC: 508448 AN: 1096744

Other (OTH) AF: 0.490 AC: 29304 AN: 59822

GnomAD4 genome AF: 0.559 AC: 85097 AN: 152156 Hom.: 25399 Cov.: 33 AF XY: 0.560 AC XY: 41658 AN XY: 74388

African (AFR) AF: 0.786 AC: 32653 AN: 41528

American (AMR) AF: 0.469 AC: 7175 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1613 AN: 3470

East Asian (EAS) AF: 0.390 AC: 2014 AN: 5164

South Asian (SAS) AF: 0.480 AC: 2317 AN: 4826

European-Finnish (FIN) AF: 0.527 AC: 5585 AN: 10592

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32024 AN: 67976

Other (OTH) AF: 0.522 AC: 1101 AN: 2108

Alfa AF: 0.465 Hom.: 3196

Bravo AF: 0.569

Asia WGS AF: 0.459 AC: 1594 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Mitochondrial DNA depletion syndrome 4b (1)
-	-	1	not specified (1)
-	-	1	POLG-related disorder (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (1)
-	-	1	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2072267; hg19: chr15-89867154; COSMIC: COSV51521765; COSMIC: COSV51521765;