rs2307448

Variant names:

• chr15-89321860-G-A
• rs2307448
• NM_002693.3:c.2481-7C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89321860-G-A
• chr15-89321860-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000268124.11(POLG):​c.2481-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,612,058 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (21 hom.)
• Consequence: POLG ENST00000268124.11 splice_region, intron
• Scores: Splicing: ADA: 0.0002760
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:14
• Conservation: PhyloP100: 0.0640
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-89321860-G-A is Benign according to our data. Variant chr15-89321860-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138747.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000268124.11. 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.2481-7C>T		splice_region intron	N/A	NP_002684.1
	POLG	NM_001126131.2		c.2481-7C>T		splice_region intron	N/A	NP_001119603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.2481-7C>T		splice_region intron	N/A	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.2481-7C>T		splice_region intron	N/A	ENSP00000399851.2
	POLG	ENST00000532584.5	TSL:3	n.623C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00247 AC: 621 AN: 251400 AF XY: 0.00258

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00468

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00472 AC: 6891 AN: 1459788 Hom.: 21 Cov.: 31 AF XY: 0.00468 AC XY: 3396 AN XY: 726384

African (AFR) AF: 0.000568 AC: 19 AN: 33464

American (AMR) AF: 0.000470 AC: 21 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000963 AC: 83 AN: 86204

European-Finnish (FIN) AF: 0.000693 AC: 37 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00586 AC: 6510 AN: 1110102

Other (OTH) AF: 0.00323 AC: 195 AN: 60312

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74448

African (AFR) AF: 0.00111 AC: 46 AN: 41538

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00534 AC: 363 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00400 Hom.: 0

Bravo AF: 0.00270

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00539

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	3	not specified (3)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	POLG-related disorder (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.1
DANN	Benign	0.83
PhyloP100		0.064
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.0080
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: rs2307448; hg19: chr15-89865091;