rs12221039

Positions:

• chr10-68430398-A-G

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.2208+38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,421,920 control chromosomes in the GnomAD database, including 9,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1002 hom., cov: 31)
  • Exomes 𝑓: 0.11 (8983 hom.)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.29

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 (BayesDel_noAF=-0.81).
• BP6: Variant 10-68430398-A-G is Benign according to our data. Variant chr10-68430398-A-G is described in ClinVar as [Benign]. Clinvar id is 1233228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNA2	NM_001080449.3	c.2208+38T>C		intron_variant		ENST00000358410.8	NP_001073918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8	c.2208+38T>C		intron_variant		1	NM_001080449.3	ENSP00000351185.3
DNA2	ENST00000551118.6	c.1983+1464T>C		intron_variant		5		ENSP00000450393.3
DNA2	ENST00000440722.2	c.171+38T>C		intron_variant		1		ENSP00000389713.1
DNA2	ENST00000399179.6	n.*29+38T>C		intron_variant		2		ENSP00000382132.3

Frequencies

GnomAD3 genomes AF: 0.0936 AC: 14235 AN: 152090 Hom.: 999 Cov.: 31

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0959

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.148 AC: 23658 AN: 160224 Hom.: 2241 AF XY: 0.151 AC XY: 12754 AN XY: 84692

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.0971

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.107 AC: 136331 AN: 1269712 Hom.: 8983 Cov.: 18 AF XY: 0.111 AC XY: 70350 AN XY: 632202

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0909

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.0936 AC: 14248 AN: 152208 Hom.: 1002 Cov.: 31 AF XY: 0.0999 AC XY: 7430 AN XY: 74404

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.0958

Gnomad4 OTH AF: 0.108

Alfa AF: 0.107 Hom.: 219

Bravo AF: 0.0903

Asia WGS AF: 0.180 AC: 627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.80

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: rs12221039; hg19: chr10-70190155; COSMIC: COSV64428153;