rs2281699

Variant names:

• chr10-68471576-C-G
• rs2281699
• NM_001080449.3:c.74+215G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-68471576-C-G
• chr10-68471576-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001080449.3(DNA2):​c.74+215G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 151,916 control chromosomes in the GnomAD database, including 7,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (7231 hom., cov: 32)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0600
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 10-68471576-C-G is Benign according to our data. Variant chr10-68471576-C-G is described in ClinVar as [Benign]. Clinvar id is 669863.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNA2	NM_001080449.3	c.74+215G>C		intron_variant	Intron 1 of 20	ENST00000358410.8	NP_001073918.2
DNA2	NR_102264.2	n.163+215G>C		intron_variant	Intron 2 of 21
DNA2	XM_006717680.3	c.164+215G>C		intron_variant	Intron 2 of 21		XP_006717743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8	c.74+215G>C		intron_variant	Intron 1 of 20	1	NM_001080449.3	ENSP00000351185.3
DNA2	ENST00000551118.6	c.74+215G>C		intron_variant	Intron 1 of 16	5		ENSP00000450393.3
DNA2	ENST00000399179.6	n.74+215G>C		intron_variant	Intron 2 of 21	2		ENSP00000382132.3
DNA2	ENST00000550357.1	n.74+215G>C		intron_variant	Intron 1 of 3	4		ENSP00000450014.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44580 AN: 151798 Hom.: 7200 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.294 AC: 44673 AN: 151916 Hom.: 7231 Cov.: 32 AF XY: 0.295 AC XY: 21928 AN XY: 74248

African (AFR) AF: 0.420 AC: 17371 AN: 41406

American (AMR) AF: 0.302 AC: 4605 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 771 AN: 3472

East Asian (EAS) AF: 0.397 AC: 2039 AN: 5134

South Asian (SAS) AF: 0.384 AC: 1843 AN: 4802

European-Finnish (FIN) AF: 0.275 AC: 2908 AN: 10576

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14220 AN: 67942

Other (OTH) AF: 0.300 AC: 632 AN: 2110

Alfa AF: 0.258 Hom.: 728

Bravo AF: 0.304

Asia WGS AF: 0.376 AC: 1307 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.48
PhyloP100		-0.060
PromoterAI		-0.047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2281699; hg19: chr10-70231333;