rs10823195

Variant names:

• chr10-68430177-A-G
• rs10823195
• NM_001080449.3:c.2208+259T>C

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.2208+259T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 151,996 control chromosomes in the GnomAD database, including 1,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1477 hom., cov: 31)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57
• Publications: 4 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=-0.93).
• BP6: Variant 10-68430177-A-G is Benign according to our data. Variant chr10-68430177-A-G is described in ClinVar as Benign. ClinVar VariationId is 671067.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	NM_001080449.3	MANE Select	c.2208+259T>C		intron	N/A	NP_001073918.2
	DNA2	NR_102264.2		n.2182+259T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.2208+259T>C		intron	N/A	ENSP00000351185.3
	DNA2	ENST00000551118.6	TSL:5	c.1983+1685T>C		intron	N/A	ENSP00000450393.3
	DNA2	ENST00000440722.2	TSL:1	c.171+259T>C		intron	N/A	ENSP00000389713.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19332 AN: 151878 Hom.: 1460 Cov.: 31

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0906

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0978

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.128 AC: 19381 AN: 151996 Hom.: 1477 Cov.: 31 AF XY: 0.127 AC XY: 9421 AN XY: 74302

African (AFR) AF: 0.196 AC: 8143 AN: 41460

American (AMR) AF: 0.0907 AC: 1381 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 411 AN: 3466

East Asian (EAS) AF: 0.250 AC: 1289 AN: 5164

South Asian (SAS) AF: 0.124 AC: 600 AN: 4820

European-Finnish (FIN) AF: 0.0978 AC: 1034 AN: 10574

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0905 AC: 6152 AN: 67970

Other (OTH) AF: 0.123 AC: 260 AN: 2110

Alfa AF: 0.0938 Hom.: 1036

Bravo AF: 0.133

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.17
PhyloP100		-1.6
PromoterAI		0.018	Neutral
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: rs10823195; hg19: chr10-70189934;