rs10998205

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.357G>A(p.Leu119Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,610,440 control chromosomes in the GnomAD database, including 10,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 945 hom., cov: 32)

Exomes 𝑓: 0.10 ( 9613 hom. )

Consequence

DNA2
NM_001080449.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.36

Publications

16 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=-0.78).

BP6

Variant 10-68468207-C-T is Benign according to our data. Variant chr10-68468207-C-T is described in ClinVar as Benign. ClinVar VariationId is 257345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNA2	NM_001080449.3 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 21	ENST00000358410.8	NP_001073918.2
DNA2	XM_006717680.3 link	c.447G>A	p.Leu149Leu	synonymous_variant	Exon 4 of 22		XP_006717743.1
DNA2	NR_102264.2 link	n.446G>A		non_coding_transcript_exon_variant	Exon 4 of 22
DNA2	XM_017015799.1 link	c.-170G>A		5_prime_UTR_variant	Exon 1 of 18		XP_016871288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 21	1	NM_001080449.3	ENSP00000351185.3
DNA2	ENST00000551118.6 link	c.357G>A	p.Leu119Leu	synonymous_variant	Exon 3 of 17	5		ENSP00000450393.3

Frequencies

GnomAD3 genomes

AF:

0.0922

AC:

14014

AN:

152022

Hom.:

940

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.0914

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0894

Gnomad OTH

AF:

0.114

GnomAD2 exomes

AF:

0.136

AC:

33500

AN:

246824

AF XY:

0.136

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.260

Gnomad ASJ exome

AF:

0.0949

Gnomad EAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.0881

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.102

AC:

148304

AN:

1458300

Hom.:

9613

Cov.:

AF XY:

0.106

AC XY:

76692

AN XY:

725208

show subpopulations

African (AFR)

AF:

0.0263

AC:

878

AN:

33426

American (AMR)

AF:

0.251

AC:

11079

AN:

44210

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

2371

AN:

26062

East Asian (EAS)

AF:

0.127

AC:

5025

AN:

39602

South Asian (SAS)

AF:

0.239

AC:

20303

AN:

85104

European-Finnish (FIN)

AF:

0.139

AC:

7381

AN:

53234

Middle Eastern (MID)

AF:

0.115

AC:

661

AN:

5760

European-Non Finnish (NFE)

AF:

0.0852

AC:

94590

AN:

1110646

Other (OTH)

AF:

0.0998

AC:

6016

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

5732

11464

17197

22929

28661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3634

7268

10902

14536

18170

<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:

0.0923

AC:

14039

AN:

152140

Hom.:

945

Cov.:

AF XY:

0.0975

AC XY:

7247

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0310

AC:

1288

AN:

41544

American (AMR)

AF:

0.171

AC:

2608

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0914

AC:

317

AN:

3468

East Asian (EAS)

AF:

0.140

AC:

723

AN:

5174

South Asian (SAS)

AF:

0.246

AC:

1189

AN:

4828

European-Finnish (FIN)

AF:

0.145

AC:

1533

AN:

10550

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0894

AC:

6076

AN:

67994

Other (OTH)

AF:

0.114

AC:

240

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

627

1255

1882

2510

3137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.0860

Hom.:

331

Bravo

AF:

0.0897

Asia WGS

AF:

0.182

AC:

634

AN:

3478

EpiCase

AF:

0.0850

EpiControl

AF:

0.0890

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 23, 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

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.24

(source)

DANN

Benign

0.53

PhyloP100

-4.4

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over