10-68465747-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001080449.3(DNA2):c.507C>A(p.Ala169Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,604,186 control chromosomes in the GnomAD database, including 50,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7304 hom., cov: 32)

Exomes 𝑓: 0.23 ( 43267 hom. )

Consequence

DNA2
NM_001080449.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.314

Publications

25 publications found

Variant links:

Genes affected

DNA2 (HGNC:2939): (DNA replication helicase/nuclease 2) This gene encodes a member of the DNA2/NAM7 helicase family. The encoded protein is a conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability. Mutations in this gene are associated with autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) and Seckel syndrome 8. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

DNA2 Gene-Disease associations (from GenCC):

mitochondrial DNA deletion syndrome with progressive myopathy
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Seckel syndrome 8
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

DNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 10-68465747-G-T is Benign according to our data. Variant chr10-68465747-G-T is described in ClinVar as Benign. ClinVar VariationId is 257346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.314 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080449.3. 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
	DNA2	NM_001080449.3	MANE Select	c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 21	NP_001073918.2
	DNA2	NR_102264.2		n.596C>A		non_coding_transcript_exon	Exon 5 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNA2	ENST00000358410.8	TSL:1 MANE Select	c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 21	ENSP00000351185.3
DNA2	ENST00000551118.6	TSL:5	c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 17	ENSP00000450393.3
DNA2	ENST00000399179.6	TSL:2	n.507C>A		non_coding_transcript_exon	Exon 5 of 22	ENSP00000382132.3

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44735

AN:

151842

Hom.:

7276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.301

Gnomad ASJ

AF:

0.220

Gnomad EAS

AF:

0.395

Gnomad SAS

AF:

0.381

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.296

GnomAD2 exomes

AF:

0.280

AC:

68446

AN:

244024

AF XY:

0.276

show subpopulations

Gnomad AFR exome

AF:

0.423

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.220

Gnomad EAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.205

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.233

AC:

338821

AN:

1452228

Hom.:

43267

Cov.:

AF XY:

0.237

AC XY:

171032

AN XY:

722098

show subpopulations

African (AFR)

AF:

0.424

AC:

14020

AN:

33104

American (AMR)

AF:

0.348

AC:

15143

AN:

43478

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

5577

AN:

25872

East Asian (EAS)

AF:

0.418

AC:

16492

AN:

39428

South Asian (SAS)

AF:

0.373

AC:

31320

AN:

84054

European-Finnish (FIN)

AF:

0.270

AC:

14378

AN:

53158

Middle Eastern (MID)

AF:

0.331

AC:

1897

AN:

5728

European-Non Finnish (NFE)

AF:

0.203

AC:

224801

AN:

1107492

Other (OTH)

AF:

0.254

AC:

15193

AN:

59914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

11395

22790

34186

45581

56976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8208

16416

24624

32832

41040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.295

AC:

44823

AN:

151958

Hom.:

7304

Cov.:

AF XY:

0.296

AC XY:

22008

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.424

AC:

17551

AN:

41424

American (AMR)

AF:

0.301

AC:

4593

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

764

AN:

3470

East Asian (EAS)

AF:

0.395

AC:

2043

AN:

5168

South Asian (SAS)

AF:

0.381

AC:

1838

AN:

4822

European-Finnish (FIN)

AF:

0.275

AC:

2909

AN:

10566

Middle Eastern (MID)

AF:

0.277

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.209

AC:

14216

AN:

67964

Other (OTH)

AF:

0.299

AC:

627

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1550

3100

4649

6199

7749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

448

896

1344

1792

2240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.227

Hom.:

4568

Bravo

AF:

0.305

Asia WGS

AF:

0.373

AC:

1295

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 02, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Seckel syndrome 8

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mitochondrial DNA deletion syndrome with progressive myopathy

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

6.1

(source)

DANN

Benign

0.73

PhyloP100

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over