rs12221039

Variant names:

• chr10-68430398-A-G
• rs12221039
• NM_001080449.3:c.2208+38T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 (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 VariationId 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 rank	MANE	Protein	UniProt
DNA2	NM_001080449.3	c.2208+38T>C		intron_variant	Intron 14 of 20	ENST00000358410.8	NP_001073918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8	c.2208+38T>C		intron_variant	Intron 14 of 20	1	NM_001080449.3	ENSP00000351185.3
DNA2	ENST00000551118.6	c.1983+1464T>C		intron_variant	Intron 13 of 16	5		ENSP00000450393.3
DNA2	ENST00000440722.2	c.171+38T>C		intron_variant	Intron 1 of 6	1		ENSP00000389713.1
DNA2	ENST00000399179.6	n.*29+38T>C		intron_variant	Intron 15 of 21	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

GnomAD2 exomes AF: 0.148 AC: 23658 AN: 160224 AF XY: 0.151

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 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

African (AFR) AF: 0.0155 AC: 451 AN: 29146

American (AMR) AF: 0.235 AC: 8053 AN: 34244

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4341 AN: 23924

East Asian (EAS) AF: 0.123 AC: 4462 AN: 36276

South Asian (SAS) AF: 0.240 AC: 18038 AN: 75296

European-Finnish (FIN) AF: 0.147 AC: 6856 AN: 46616

Middle Eastern (MID) AF: 0.101 AC: 524 AN: 5174

European-Non Finnish (NFE) AF: 0.0909 AC: 87768 AN: 965344

Other (OTH) AF: 0.109 AC: 5838 AN: 53692

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

African (AFR) AF: 0.0191 AC: 792 AN: 41564

American (AMR) AF: 0.164 AC: 2505 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3468

East Asian (EAS) AF: 0.137 AC: 711 AN: 5180

South Asian (SAS) AF: 0.242 AC: 1168 AN: 4826

European-Finnish (FIN) AF: 0.156 AC: 1650 AN: 10572

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0958 AC: 6519 AN: 68014

Other (OTH) AF: 0.108 AC: 229 AN: 2112

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

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	-0.81
CADD	Benign	7.9
DANN	Benign	0.80
PhyloP100		2.3
PromoterAI		0.010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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