10-68415128-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001080449.3(DNA2):c.3115-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,454,880 control chromosomes in the GnomAD database, including 10,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.094 (1001 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9486 hom.)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-68415128-A-G is Benign according to our data. Variant chr10-68415128-A-G is described in ClinVar as [Benign]. Clinvar id is 1292160.Status of the report is criteria_provided_single_submitter, 1 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	UniProt
DNA2	NM_001080449.3	c.3115-21T>C		intron_variant		ENST00000358410.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNA2	ENST00000358410.8	c.3115-21T>C		intron_variant		1	NM_001080449.3	P1
DNA2	ENST00000551118.6	c.2403-21T>C		intron_variant		5
DNA2	ENST00000399179.6	c.*936-21T>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14254 AN: 152066 Hom.: 998 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0961

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.153 AC: 24868 AN: 162728 Hom.: 2451 AF XY: 0.156 AC XY: 13406 AN XY: 86192

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.0988

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.109 AC: 142459 AN: 1302696 Hom.: 9486 Cov.: 21 AF XY: 0.113 AC XY: 73368 AN XY: 648214

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0927

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.0937 AC: 14267 AN: 152184 Hom.: 1001 Cov.: 32 AF XY: 0.0999 AC XY: 7433 AN XY: 74388

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.0961

Gnomad4 OTH AF: 0.107

Alfa AF: 0.108 Hom.: 221

Bravo AF: 0.0906

Asia WGS AF: 0.177 AC: 618 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	8.9
Dann	Benign	0.88

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: rs17460571; hg19: chr10-70174885; COSMIC: COSV64427844; COSMIC: COSV64427844;