10-68465747-G-T

Variant names:

• chr10-68465747-G-T
• rs3758626
• NM_001080449.3:c.507C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080449.3(DNA2):​c.507C>A​(p.Ala169Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,604,186 control chromosomes in the GnomAD database, including 50,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7304 hom., cov: 32)
  • Exomes 𝑓: 0.23 (43267 hom.)
• Consequence: DNA2 NM_001080449.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.314
• Publications: 25 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Seckel syndrome 8

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 10-68465747-G-T is Benign according to our data. Variant chr10-68465747-G-T is described in ClinVar as Benign. ClinVar VariationId is 257346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080449.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	NM_001080449.3	MANE Select	c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 21	NP_001073918.2	P51530-1
	DNA2	NR_102264.2		n.596C>A		non_coding_transcript_exon	Exon 5 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 21	ENSP00000351185.3	P51530-1
	DNA2	ENST00000551118.6	TSL:5	c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 17	ENSP00000450393.3	F8VR31
	DNA2	ENST00000936797.1		c.507C>A	p.Ala169Ala	synonymous	Exon 4 of 22	ENSP00000606856.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44735 AN: 151842 Hom.: 7276 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.296

GnomAD2 exomes AF: 0.280 AC: 68446 AN: 244024 AF XY: 0.276

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.233 AC: 338821 AN: 1452228 Hom.: 43267 Cov.: 31 AF XY: 0.237 AC XY: 171032 AN XY: 722098

African (AFR) AF: 0.424 AC: 14020 AN: 33104

American (AMR) AF: 0.348 AC: 15143 AN: 43478

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5577 AN: 25872

East Asian (EAS) AF: 0.418 AC: 16492 AN: 39428

South Asian (SAS) AF: 0.373 AC: 31320 AN: 84054

European-Finnish (FIN) AF: 0.270 AC: 14378 AN: 53158

Middle Eastern (MID) AF: 0.331 AC: 1897 AN: 5728

European-Non Finnish (NFE) AF: 0.203 AC: 224801 AN: 1107492

Other (OTH) AF: 0.254 AC: 15193 AN: 59914

GnomAD4 genome AF: 0.295 AC: 44823 AN: 151958 Hom.: 7304 Cov.: 32 AF XY: 0.296 AC XY: 22008 AN XY: 74286

African (AFR) AF: 0.424 AC: 17551 AN: 41424

American (AMR) AF: 0.301 AC: 4593 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3470

East Asian (EAS) AF: 0.395 AC: 2043 AN: 5168

South Asian (SAS) AF: 0.381 AC: 1838 AN: 4822

European-Finnish (FIN) AF: 0.275 AC: 2909 AN: 10566

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.209 AC: 14216 AN: 67964

Other (OTH) AF: 0.299 AC: 627 AN: 2098

Alfa AF: 0.227 Hom.: 4568

Bravo AF: 0.305

Asia WGS AF: 0.373 AC: 1295 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Mitochondrial DNA deletion syndrome with progressive myopathy (1)
-	-	1	Seckel syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.1
DANN	Benign	0.73
PhyloP100		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs3758626; hg19: chr10-70225504; COSMIC: COSV63063099; COSMIC: COSV63063099;