10-68422577-GAA-TAG

Variant names:

• chr10-68422577-GAA-TAG
• NM_001080449.3:c.2428_2430delTTCinsCTA
• DNA2 p.Phe810Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001080449.3(DNA2):​c.2428_2430delTTCinsCTA​(p.Phe810Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F810F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNA2 NM_001080449.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.2428_2430delTTCinsCTA	p.Phe810Leu	missense	N/A	NP_001073918.2	P51530-1
	DNA2	NR_102264.2		n.2402_2404delTTCinsCTA		non_coding_transcript_exon	Exon 17 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.2428_2430delTTCinsCTA	p.Phe810Leu	missense	N/A	ENSP00000351185.3	P51530-1
	DNA2	ENST00000440722.2	TSL:1	c.391_393delTTCinsCTA	p.Phe131Leu	missense	N/A	ENSP00000389713.1	H0Y455
	DNA2	ENST00000551118.6	TSL:5	c.1984-2687_1984-2685delTTCinsCTA		intron	N/A	ENSP00000450393.3	F8VR31

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-70182334;