rs181679245

Variant names:

• chr10-68419877-G-T
• rs181679245
• NM_001080449.3:c.2713C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77
• Publications: 10 publications found

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

ACMG classification

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 Benign/Likely_benign. ClinVar VariationId 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

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.2713C>A	p.Gln905Lys	missense	Exon 18 of 21	NP_001073918.2
	DNA2	NR_102264.2		n.2687C>A		non_coding_transcript_exon	Exon 19 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.2713C>A	p.Gln905Lys	missense	Exon 18 of 21	ENSP00000351185.3
	DNA2	ENST00000551118.6	TSL:5	c.1999C>A	p.Gln667Lys	missense	Exon 14 of 17	ENSP00000450393.3
	DNA2	ENST00000440722.2	TSL:1	c.676C>A	p.Gln226Lys	missense	Exon 5 of 7	ENSP00000389713.1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 667 AN: 152114 Hom.: 5 Cov.: 32

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

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.: 45 Cov.: 30 AF XY: 0.00688 AC XY: 4998 AN XY: 726958

African (AFR) AF: 0.000836 AC: 28 AN: 33478

American (AMR) AF: 0.00161 AC: 72 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86238

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00897 AC: 9971 AN: 1111572

Other (OTH) AF: 0.00527 AC: 318 AN: 60356

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152232 Hom.: 5 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74418

African (AFR) AF: 0.00156 AC: 65 AN: 41550

American (AMR) AF: 0.00196 AC: 30 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00791 AC: 538 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00655 Hom.: 8

Bravo AF: 0.00430

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00192 AC: 7

ESP6500EA AF: 0.00919 AC: 75

ExAC AF: 0.00445 AC: 538

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00640

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.34
Sift	Benign	0.43	T
Sift4G	Benign	0.63	T
Polyphen		0.96	D
Vest4		0.11
MVP		0.87
ClinPred		0.022	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.35
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs181679245; hg19: chr10-70179634; COSMIC: COSV106106668; COSMIC: COSV106106668;