rs190301454

Variant names:

• chr10-68422207-A-G
• rs190301454
• NM_001080449.3:c.2697+18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080449.3(DNA2):​c.2697+18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,505,636 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0160
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-68422207-A-G is Benign according to our data. Variant chr10-68422207-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000431 (64/148580) while in subpopulation AMR AF = 0.00243 (37/15220). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.2697+18T>C		intron	N/A	NP_001073918.2	P51530-1
	DNA2	NR_102264.2		n.2671+18T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.2697+18T>C		intron	N/A	ENSP00000351185.3	P51530-1
	DNA2	ENST00000551118.6	TSL:5	c.1984-2315T>C		intron	N/A	ENSP00000450393.3	F8VR31
	DNA2	ENST00000440722.2	TSL:1	c.660+18T>C		intron	N/A	ENSP00000389713.1	H0Y455

Frequencies

GnomAD3 genomes AF: 0.000431 AC: 64 AN: 148472 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.000497 AC: 74 AN: 148986 AF XY: 0.000448

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000375

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000337 AC: 457 AN: 1357056 Hom.: 2 Cov.: 25 AF XY: 0.000351 AC XY: 235 AN XY: 670140

African (AFR) AF: 0.000135 AC: 4 AN: 29580

American (AMR) AF: 0.00183 AC: 46 AN: 25186

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 28 AN: 22126

East Asian (EAS) AF: 0.00 AC: 0 AN: 37836

South Asian (SAS) AF: 0.00 AC: 0 AN: 72904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49550

Middle Eastern (MID) AF: 0.00331 AC: 18 AN: 5436

European-Non Finnish (NFE) AF: 0.000281 AC: 297 AN: 1058234

Other (OTH) AF: 0.00114 AC: 64 AN: 56204

GnomAD4 genome AF: 0.000431 AC: 64 AN: 148580 Hom.: 0 Cov.: 32 AF XY: 0.000467 AC XY: 34 AN XY: 72732

African (AFR) AF: 0.000132 AC: 5 AN: 37936

American (AMR) AF: 0.00243 AC: 37 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.00191 AC: 4 AN: 2098

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000684

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.53
PhyloP100		0.016
Mutation Taster		=100/0	polymorphism

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: rs190301454; hg19: chr10-70181964;