10-68468207-C-T

Position:

• chr10-68468207-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080449.3(DNA2):​c.357G>A​(p.Leu119Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,610,440 control chromosomes in the GnomAD database, including 10,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (945 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9613 hom.)
• Consequence: DNA2 NM_001080449.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.36

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-68468207-C-T is Benign according to our data. Variant chr10-68468207-C-T is described in ClinVar as [Benign]. Clinvar id is 257345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68468207-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNA2	NM_001080449.3	c.357G>A	p.Leu119Leu	synonymous_variant	3/21	ENST00000358410.8	NP_001073918.2
DNA2	XM_006717680.3	c.447G>A	p.Leu149Leu	synonymous_variant	4/22		XP_006717743.1
DNA2	XM_017015799.1	c.-170G>A		5_prime_UTR_variant	1/18		XP_016871288.1
DNA2	NR_102264.2	n.446G>A		non_coding_transcript_exon_variant	4/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8	c.357G>A	p.Leu119Leu	synonymous_variant	3/21	1	NM_001080449.3	ENSP00000351185.3
DNA2	ENST00000551118.6	c.357G>A	p.Leu119Leu	synonymous_variant	3/17	5		ENSP00000450393.3

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14014 AN: 152022 Hom.: 940 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0894

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.136 AC: 33500 AN: 246824 Hom.: 3117 AF XY: 0.136 AC XY: 18258 AN XY: 133920

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.0949

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.0881

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.102 AC: 148304 AN: 1458300 Hom.: 9613 Cov.: 31 AF XY: 0.106 AC XY: 76692 AN XY: 725208

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.0910

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.0852

Gnomad4 OTH exome AF: 0.0998

GnomAD4 genome AF: 0.0923 AC: 14039 AN: 152140 Hom.: 945 Cov.: 32 AF XY: 0.0975 AC XY: 7247 AN XY: 74356

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.0914

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.0894

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0865 Hom.: 331

Bravo AF: 0.0897

Asia WGS AF: 0.182 AC: 634 AN: 3478

EpiCase AF: 0.0850

EpiControl AF: 0.0890

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.24
DANN	Benign	0.53

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: rs10998205; hg19: chr10-70227964; COSMIC: COSV64427426;