10-68414950-T-A

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.*89A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 831,374 control chromosomes in the GnomAD database, including 36,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6149 hom., cov: 32)
  • Exomes 𝑓: 0.29 (30131 hom.)
• Consequence: DNA2 NM_001080449.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.493

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 (MetaRNN=0.0015733242).
• BP6: Variant 10-68414950-T-A is Benign according to our data. Variant chr10-68414950-T-A is described in ClinVar as [Benign]. Clinvar id is 1182638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNA2	NM_001080449.3	c.*89A>T		3_prime_UTR_variant	21/21	ENST00000358410.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNA2	ENST00000358410.8	c.*89A>T		3_prime_UTR_variant	21/21	1	NM_001080449.3	P1
DNA2	ENST00000551118.6	c.2560A>T	p.Met854Leu	missense_variant	17/17	5
DNA2	ENST00000399179.6			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42601 AN: 151878 Hom.: 6146 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.294 AC: 199869 AN: 679378 Hom.: 30131 Cov.: 9 AF XY: 0.290 AC XY: 101519 AN XY: 349936

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.280 AC: 42607 AN: 151996 Hom.: 6149 Cov.: 32 AF XY: 0.287 AC XY: 21298 AN XY: 74254

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.251

Alfa AF: 0.211 Hom.: 583

Bravo AF: 0.270

TwinsUK AF: 0.304 AC: 1126

ALSPAC AF: 0.291 AC: 1121

Asia WGS AF: 0.191 AC: 667 AN: 3472

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 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.1
Dann	Benign	0.46
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0016	T
MutationTaster	Benign	1.0	P;P;P
Vest4		0.27
MVP		0.40
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1801041; hg19: chr10-70174707; COSMIC: COSV64427714; COSMIC: COSV64427714;