10-68446241-A-C

Variant names:

• chr10-68446241-A-C
• rs2052037620
• NM_001080449.3:c.1057+55T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080449.3(DNA2):​c.1057+55T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 743,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.799
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.1057+55T>G		intron	N/A	NP_001073918.2	P51530-1
	DNA2	NR_102264.2		n.1146+55T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.1057+55T>G		intron	N/A	ENSP00000351185.3	P51530-1
	DNA2	ENST00000551118.6	TSL:5	c.1057+55T>G		intron	N/A	ENSP00000450393.3	F8VR31
	DNA2	ENST00000936797.1		c.1150+55T>G		intron	N/A	ENSP00000606856.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000134 AC: 1 AN: 743814 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 389504

African (AFR) AF: 0.00 AC: 0 AN: 17994

American (AMR) AF: 0.0000357 AC: 1 AN: 27998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19394

East Asian (EAS) AF: 0.00 AC: 0 AN: 31426

South Asian (SAS) AF: 0.00 AC: 0 AN: 62024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 504898

Other (OTH) AF: 0.00 AC: 0 AN: 35362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.6
DANN	Benign	0.54
PhyloP100		0.80

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: rs2052037620; hg19: chr10-70205998;