rs181679245

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080449.3(DNA2):c.2713C>A(p.Gln905Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00695 in 1,613,568 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 45 hom. )

Consequence

DNA2
NM_001080449.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.77

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073437393).

BP6

Variant 10-68419877-G-T is Benign according to our data. Variant chr10-68419877-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00438 (667/152232) while in subpopulation NFE AF = 0.00791 (538/68016). AF 95% confidence interval is 0.00736. There are 5 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNA2	NM_001080449.3 link	c.2713C>A	p.Gln905Lys	missense_variant	Exon 18 of 21	ENST00000358410.8	NP_001073918.2	P51530-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8 link	c.2713C>A	p.Gln905Lys	missense_variant	Exon 18 of 21	1	NM_001080449.3	ENSP00000351185.3		P51530-1
DNA2	ENST00000551118.6 link	c.1999C>A	p.Gln667Lys	missense_variant	Exon 14 of 17	5		ENSP00000450393.3		F8VR31

Frequencies

GnomAD3 genomes

AF:

0.00438

AC:

667

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00791

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00421

AC:

1048

AN:

249186

AF XY:

0.00405

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00798

Gnomad OTH exome

AF:

0.00380

GnomAD4 exome

AF:

0.00722

AC:

10548

AN:

1461336

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

4998

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33478

American (AMR)

AF:

0.00161

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00210

AC:

112

AN:

53392

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00897

AC:

9971

AN:

1111572

Other (OTH)

AF:

0.00527

AC:

318

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

495

990

1485

1980

2475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00438

AC:

667

AN:

152232

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41550

American (AMR)

AF:

0.00196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00791

AC:

538

AN:

68016

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00655

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00192

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00445

AC:

538

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23859901) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA2: PP2, BP4, BS2 -

May 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 27, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 18, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.011

T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L

PhyloP100

1.8

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.91

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.43

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.96

D;B

Vest4

0.11

MVP

0.87

ClinPred

0.022

GERP RS

5.9

Varity_R

0.15

gMVP

0.35

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs181679245

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over