10-68416739-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001080449.3(DNA2):c.3084G>T(p.Lys1028Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNA2 NM_001080449.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNA2	NM_001080449.3	c.3084G>T	p.Lys1028Asn	missense_variant	20/21	ENST00000358410.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNA2	ENST00000358410.8	c.3084G>T	p.Lys1028Asn	missense_variant	20/21	1	NM_001080449.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 07, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.038	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	0.94	D;D;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		1.0	D;P
Vest4		0.62
MutPred		0.36		.;Loss of methylation at K1028 (P = 0.0244);
MVP		0.93
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.38
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-70176496;