rs75569266

chr10-68419808-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080449.3(DNA2):c.2782G>A(p.Val928Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,612,212 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (196 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (194 hom.)
• Consequence: DNA2 NM_001080449.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015122294).
• BP6: Variant 10-68419808-C-T is Benign according to our data. Variant chr10-68419808-C-T is described in ClinVar as [Benign]. Clinvar id is 257344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNA2	NM_001080449.3	c.2782G>A	p.Val928Ile	missense_variant	18/21	ENST00000358410.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNA2	ENST00000358410.8	c.2782G>A	p.Val928Ile	missense_variant	18/21	1	NM_001080449.3	P1
DNA2	ENST00000440722.2	c.748G>A	p.Val250Ile	missense_variant	5/7	1
DNA2	ENST00000551118.6	c.2068G>A	p.Val690Ile	missense_variant	14/17	5
DNA2	ENST00000399179.6	c.*603G>A		3_prime_UTR_variant, NMD_transcript_variant	19/22	2

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4427 AN: 152088 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.00728 AC: 1811 AN: 248926 Hom.: 81 AF XY: 0.00523 AC XY: 706 AN XY: 135038

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00555

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00285 AC: 4155 AN: 1460006 Hom.: 194 Cov.: 30 AF XY: 0.00242 AC XY: 1756 AN XY: 726406

Gnomad4 AFR exome AF: 0.0990

Gnomad4 AMR exome AF: 0.00607

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00688

GnomAD4 genome AF: 0.0291 AC: 4434 AN: 152206 Hom.: 196 Cov.: 32 AF XY: 0.0274 AC XY: 2041 AN XY: 74428

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.00519 Hom.: 51

Bravo AF: 0.0338

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0987 AC: 358

ESP6500EA AF: 0.000491 AC: 4

ExAC AF: 0.00873 AC: 1055

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	11
Dann	Benign	0.51
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.17
Sift	Benign	0.71	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.054	B;B
Vest4		0.12
MVP		0.35
ClinPred		0.0077	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.088

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

LitVar

Other links and lift over

dbSNP: rs75569266; hg19: chr10-70179565;