rs181679245

Positions:

chr10-68419877-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000358410.8(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. 13/20 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
ENST00000358410.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.77

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr10-68419877-G-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNA2	NM_001080449.3 linkuse as main transcript	c.2713C>A	p.Gln905Lys	missense_variant	18/21	ENST00000358410.8	NP_001073918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8 linkuse as main transcript	c.2713C>A	p.Gln905Lys	missense_variant	18/21	1	NM_001080449.3	ENSP00000351185	P1	P51530-1
DNA2	ENST00000440722.2 linkuse as main transcript	c.679C>A	p.Gln227Lys	missense_variant	5/7	1		ENSP00000389713
DNA2	ENST00000551118.6 linkuse as main transcript	c.1999C>A	p.Gln667Lys	missense_variant	14/17	5		ENSP00000450393
DNA2	ENST00000399179.6 linkuse as main transcript	c.*534C>A		3_prime_UTR_variant, NMD_transcript_variant	19/22	2		ENSP00000382132		P51530-2

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

GnomAD3 exomes

AF:

0.00421

AC:

1048

AN:

249186

Hom.:

AF XY:

0.00405

AC XY:

548

AN XY:

135186

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 SAS 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

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00161

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00210

Gnomad4 NFE exome

AF:

0.00897

Gnomad4 OTH exome

AF:

0.00527

GnomAD4 genome

AF:

0.00438

AC:

667

AN:

152232

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.00791

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00682

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DNA2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	This variant is associated with the following publications: (PMID: 23859901) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 27, 2020

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

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

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

MutationTaster

Benign

0.94

N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over